View source for C-Raf

{{Short description|Mammalian protein found in Homo sapiens}}
{{cs1 config|name-list-style=vanc}}{{Redirect|RAF1|the aircraft engine|RAF 1}}
{{lowercase|title=c-Raf}}
{{Infobox_gene}}
'''RAF proto-oncogene serine/threonine-protein kinase''', also known as '''proto-oncogene c-RAF''' or simply '''c-Raf''' or even '''Raf-1''', is an [[enzyme]]<ref name="pmid1846778">{{cite journal | vauthors = Li P, Wood K, Mamon H, Haser W, Roberts T | title = Raf-1: a kinase currently without a cause but not lacking in effects | journal = Cell | volume = 64 | issue = 3 | pages = 479–82 | date = February 1991 | pmid = 1846778 | doi = 10.1016/0092-8674(91)90228-Q | s2cid = 37427156 }}</ref> that in humans is [[genetic code|encoded]] by the ''RAF1'' [[gene]].<ref name="pmid6308607">{{cite journal | vauthors = Rapp UR, Goldsborough MD, Mark GE, Bonner TI, Groffen J, Reynolds FH, Stephenson JR | title = Structure and biological activity of v-raf, a unique oncogene transduced by a retrovirus | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 80 | issue = 14 | pages = 4218–22 | date = July 1983 | pmid = 6308607 | pmc = 384008 | doi = 10.1073/pnas.80.14.4218 | bibcode = 1983PNAS...80.4218R | doi-access = free }}</ref><ref name="pmid6691137">{{cite journal | vauthors = Bonner T, O'Brien SJ, Nash WG, Rapp UR, Morton CC, Leder P | title = The human homologs of the raf (mil) oncogene are located on human chromosomes 3 and 4 | journal = Science | volume = 223 | issue = 4631 | pages = 71–4 | date = January 1984 | pmid = 6691137 | doi = 10.1126/science.6691137 | bibcode = 1984Sci...223...71B }}</ref> The c-Raf protein is part of the [[MAPK/ERK pathway|ERK1/2 pathway]] as a MAP kinase (MAP3K) that functions downstream of the [[Ras subfamily]] of membrane associated GTPases.<ref>{{cite web | title = Entrez Gene: RAF1 v-raf-1 murine leukemia viral oncogene homolog 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5894}}</ref> C-Raf is a member of the [[Raf kinase]] family of [[serine/threonine-specific protein kinase]]s, from the TKL (Tyrosine-kinase-like) group of kinases.

==Discovery==

The first Raf gene, '''v-Raf''' was found in 1983. It was isolated from the murine [[retrovirus]] bearing the number 3611. It was soon demonstrated to be capable to transform rodent fibroblasts to cancerous [[Immortalised cell line|cell lines]], so this gene was given the name Virus-induced Rapidly Accelerated Fibrosarcoma (V-RAF).<ref name="pmid6308607"/> A year later, another transforming gene was found in the avian retrovirus MH2, named v-Mil - that turned out to be highly similar to v-Raf.<ref name="pmid6325930">{{cite journal | vauthors = Sutrave P, Bonner TI, Rapp UR, Jansen HW, Patschinsky T, Bister K | title = Nucleotide sequence of avian retroviral oncogene v-mil: homologue of murine retroviral oncogene v-raf | journal = Nature | volume = 309 | issue = 5963 | pages = 85–8 | year = 1984 | pmid = 6325930 | doi = 10.1038/309085a0 | bibcode = 1984Natur.309...85S | s2cid = 4357047 }}</ref> Researchers were able to demonstrate that these genes encode enzymes that have serine-threonine kinase activity.<ref name="pmid6438534">{{cite journal | vauthors = Moelling K, Heimann B, Beimling P, Rapp UR, Sander T | title = Serine- and threonine-specific protein kinase activities of purified gag-mil and gag-raf proteins | journal = Nature | volume = 312 | issue = 5994 | pages = 558–61 | year = 1984 | pmid = 6438534 | doi = 10.1038/312558a0 | bibcode = 1984Natur.312..558M | s2cid = 4269749 }}</ref> Normal cellular homologs of v-Raf and v-Mil were soon found in both the mouse and chicken genome (hence the name '''c-Raf''' for the normal ''cellular'' Raf gene), and it became clear that these too had a role in regulating growth and cell division.<ref name="pmid1992343">{{cite journal | vauthors = Kolch W, Heidecker G, Lloyd P, Rapp UR | title = Raf-1 protein kinase is required for growth of induced NIH/3T3 cells | journal = Nature | volume = 349 | issue = 6308 | pages = 426–8 | date = January 1991 | pmid = 1992343 | doi = 10.1038/349426a0 | bibcode = 1991Natur.349..426K | s2cid = 4368936 | url = https://zenodo.org/record/1233091 }}</ref><ref name="pmid6324342">{{cite journal | vauthors = Mark GE, Rapp UR | title = Primary structure of v-raf: relatedness to the src family of oncogenes | journal = Science | volume = 224 | issue = 4646 | pages = 285–9 | date = April 1984 | pmid = 6324342 | doi = 10.1126/science.6324342 | bibcode = 1984Sci...224..285M }}</ref> 

c-Raf is a principal component of the [[mitogen-activated protein kinase]] (MAPK) pathway: [[MAPK/ERK pathway|ERK1/2 signaling]].<ref name="pmid1322500">{{cite journal | vauthors = Kyriakis JM, App H, Zhang XF, Banerjee P, Brautigan DL, Rapp UR, Avruch J | title = Raf-1 activates MAP kinase-kinase | journal = Nature | volume = 358 | issue = 6385 | pages = 417–21 | date = July 1992 | pmid = 1322500 | doi = 10.1038/358417a0 | bibcode = 1992Natur.358..417K | s2cid = 4335307 }}</ref> It acts as a MAP3 kinase, initiating the entire kinase cascade. Subsequent experiments showed that the normal, cellular Raf genes can also mutate to become oncogenes, by "overdriving" MEK1/2 and ERK1/2 activity.<ref name="pmid2843497">{{cite journal | vauthors = Shimizu K, Nakatsu Y, Nomoto S, Sekiguchi M | title = Structure of the activated c-raf-1 gene from human stomach cancer | journal = Int. Symp. Princess Takamatsu Cancer Res. Fund | volume = 17 | pages = 85–91 | year = 1986 | pmid = 2843497 }}</ref> In fact, vertebrate genomes contain multiple Raf genes. Several years later after the discovery of c-Raf, two further related kinases were described: [[ARAF|A-Raf]] and  [[BRAF (gene)|B-Raf]]. The latter became the focus of research in recent years, since a large portion of human tumors carry oncogenic 'driver' mutations in the B-Raf gene.<ref name="pmid12068308">{{cite journal | vauthors = Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA | title = Mutations of the BRAF gene in human cancer | journal = Nature | volume = 417 | issue = 6892 | pages = 949–54 | date = June 2002 | pmid = 12068308 | doi = 10.1038/nature00766 | url = http://eprints.gla.ac.uk/121/1/Davis%2CH_2002_pdf.pdf | bibcode = 2002Natur.417..949D | s2cid = 3071547 }}</ref> These mutations induce an uncontrolled, high activity of Raf enzymes. Thus diagnostic and therapeutic interest in Raf kinases reached a new peak in the recent years.<ref name="pmid15827342">{{cite journal | vauthors = Sridhar SS, Hedley D, Siu LL | title = Raf kinase as a target for anticancer therapeutics | journal = Mol. Cancer Ther. | volume = 4 | issue = 4 | pages = 677–85 | date = April 2005 | pmid = 15827342 | doi = 10.1158/1535-7163.MCT-04-0297 | doi-access = free }}</ref>

==Structure==

The human c-Raf gene is located on [[Chromosome 3 (human)|chromosome 3]]. At least two isoforms of [[Messenger RNA|mRNA]] have been described (arising from inclusion or removal of an [[Alternative splicing|alternative exon]]) that display only minute differences. The shorter, major isoform - consisting of 17 [[exon]]s - encodes a [[protein kinase]] of 648 amino acids.<ref name="pmid1886707">{{cite journal | vauthors = Dozier C, Ansieau S, Ferreira E, Coll J, Stehelin D | title = An alternatively spliced c-mil/raf mRNA is predominantly expressed in chicken muscular tissues and conserved among vertebrate species | journal = Oncogene | volume = 6 | issue = 8 | pages = 1307–11 | date = August 1991 | pmid = 1886707 }}</ref>

[[File:C-Raf-architecture.png|thumb|left|upright=1.5|A schematic architecture of human c-Raf protein]]
Similarly to many other [[MAP kinase kinase kinase|MAPKKKs]], c-Raf is a [[Protein domain#Multidomain proteins|multidomain protein]], with several additional [[Protein domain|domains]] to aid the regulation of its [[Enzyme|catalytic]] activity. On its N-terminal segment, a Ras-binding domain (RBD) and a C-kinase homologous domain 1 (C1 domain) are found next to each other. Structures of both conserved domains were solved in the past decades, shedding light on the mechanisms of their regulation.

The [[Raf-like Ras-binding domain|Ras-binding domain]] displays a ubiquitin-like fold (like many other small G-protein associating domains) and selectively binds GTP-bound Ras proteins only.<ref name="pmid7791872">{{cite journal | vauthors = Nassar N, Horn G, Herrmann C, Scherer A, McCormick F, Wittinghofer A | title = The 2.2 A crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue | journal = Nature | volume = 375 | issue = 6532 | pages = 554–60 | date = June 1995 | pmid = 7791872 | doi = 10.1038/375554a0 | bibcode = 1995Natur.375..554N | s2cid = 4347807 }}</ref><ref name="pmid7766599">{{cite journal | vauthors = Emerson SD, Madison VS, Palermo RE, Waugh DS, Scheffler JE, Tsao KL, Kiefer SE, Liu SP, Fry DC | title = Solution structure of the Ras-binding domain of c-Raf-1 and identification of its Ras interaction surface | journal = Biochemistry | volume = 34 | issue = 21 | pages = 6911–8 | date = May 1995 | pmid = 7766599 | doi = 10.1021/bi00021a001 }}</ref><ref name="pmid8503013">{{cite journal | vauthors = Moodie SA, Willumsen BM, Weber MJ, Wolfman A | title = Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase | journal = Science | volume = 260 | issue = 5114 | pages = 1658–61 | date = June 1993 | pmid = 8503013 | doi = 10.1126/science.8503013 | bibcode = 1993Sci...260.1658M }}</ref> (You can see this interaction in high detail in the PDB box attached to the article. It shows Rap1 in complex with the RBD of c-Raf.)

The [[C1 domain]] - immediately downstream of the Ras binding domain - is a special [[zinc finger]], rich in cysteines and stabilized by two zinc ions. It is similar to the diacylglycerol-binding C1 domains of [[protein kinase C]] (PKC) enzymes.<ref name="pmid8710867">{{cite journal | vauthors = Mott HR, Carpenter JW, Zhong S, Ghosh S, Bell RM, Campbell SL | title = The solution structure of the Raf-1 cysteine-rich domain: a novel ras and phospholipid binding site | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 16 | pages = 8312–7 | date = August 1996 | pmid = 8710867 | pmc = 38667 | doi = 10.1073/pnas.93.16.8312 | bibcode = 1996PNAS...93.8312M | doi-access = free }}</ref><ref name="pmid9774683">{{cite journal | vauthors = Daub M, Jöckel J, Quack T, Weber CK, Schmitz F, Rapp UR, Wittinghofer A, Block C | title = The RafC1 cysteine-rich domain contains multiple distinct regulatory epitopes which control Ras-dependent Raf activation | journal = Mol. Cell. Biol. | volume = 18 | issue = 11 | pages = 6698–710 | date = November 1998 | pmid = 9774683 | pmc = 109253 | doi =  10.1128/mcb.18.11.6698}}</ref> But unlike PKC, the C1 domains of Raf family kinases do not bind diacylglycerol.<ref name="pmid19710537">{{cite journal | vauthors = Yin X, Zafrullah M, Lee H, Haimovitz-Friedman A, Fuks Z, Kolesnick R | title = A ceramide-binding C1 domain mediates kinase suppressor of ras membrane translocation | journal = Cell. Physiol. Biochem. | volume = 24 | issue = 3–4 | pages = 219–30 | year = 2009 | pmid = 19710537 | pmc = 2978518 | doi = 10.1159/000233248 }}</ref> Instead, they interact with other lipids, such as ceramide<ref name="pmid19710537" /> or phosphatidic acid,<ref name="pmid18952605">{{cite journal | vauthors = Kraft CA, Garrido JL, Fluharty E, Leiva-Vega L, Romero G | title = Role of phosphatidic acid in the coupling of the ERK cascade | journal = J. Biol. Chem. | volume = 283 | issue = 52 | pages = 36636–45 | date = December 2008 | pmid = 18952605 | pmc = 2606017 | doi = 10.1074/jbc.M804633200 | doi-access = free }}</ref> and even aid in the recognition of activated Ras (GTP-Ras).<ref name="pmid9774683" /><ref name="pmid7730360">{{cite journal | vauthors = Brtva TR, Drugan JK, Ghosh S, Terrell RS, Campbell-Burk S, Bell RM, Der CJ | title = Two distinct Raf domains mediate interaction with Ras | journal = J. Biol. Chem. | volume = 270 | issue = 17 | pages = 9809–12 | date = April 1995 | pmid = 7730360 | doi = 10.1074/jbc.270.17.9809 | doi-access = free }}</ref>

The close proximity of these two domains as well as several lines of experimental data suggest that they act as a single unit to negatively regulate the activity of the protein kinase domain, by direct physical interaction.<ref name="pmid9689060">{{cite journal | vauthors = Cutler RE, Stephens RM, Saracino MR, Morrison DK | title = Autoregulation of the Raf-1 serine/threonine kinase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 16 | pages = 9214–9 | date = August 1998 | pmid = 9689060 | pmc = 21318 | doi = 10.1073/pnas.95.16.9214 | bibcode = 1998PNAS...95.9214C | doi-access = free }}</ref> Historically, this autoinhibitory block was labelled as the  CR1 region ("Conserved Region 1"), the hinge region being named CR2, and the kinase domain CR3. Unfortunately, the precise structure of the autoinhibited kinase remains unknown.

Between the autoinhibitory domain block and the catalytic kinase domain, a long segment - characteristic to all Raf proteins - can be found. It is highly enriched in [[serine]] amino acids, but its precise [[Sequence (biology)|sequence]] is poorly conserved across related Raf genes. This region appears to be intrinsically unstructured, and very flexible. Its most likely role is to act as a natural "hinge" between the rigidly folded autoinhibitory and catalytic domains, enabling complex movements and profound conformational rearrangements within the molecule.<ref name="pmid17074813">{{cite journal | vauthors = Hmitou I, Druillennec S, Valluet A, Peyssonnaux C, Eychène A | title = Differential regulation of B-raf isoforms by phosphorylation and autoinhibitory mechanisms | journal = Mol. Cell. Biol. | volume = 27 | issue = 1 | pages = 31–43 | date = January 2007 | pmid = 17074813 | pmc = 1800654 | doi = 10.1128/MCB.01265-06 }}</ref> This hinge region contains a small, conserved [[short linear motif|island]] of amino acids, that are responsible for [[14-3-3 protein]] recognition, but only when a critical serine (Ser259 in human c-Raf) is phosphorylated. A second, similar motif is found on the extreme C-terminus (centered around the phosphorylatable Ser 621) of all Raf enzymes, but downstream of the kinase domain.

The C-terminal half of c-Raf folds into a single protein domain, responsible for catalytic activity. The structure of this [[Protein kinase domain|kinase domain]] is well-known from both c-Raf<ref name="pmid20130576">{{cite journal | vauthors = Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S | title = RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth | journal = Nature | volume = 464 | issue = 7287 | pages = 431–5 | date = March 2010 | pmid = 20130576 | doi = 10.1038/nature08833 | bibcode = 2010Natur.464..431H | doi-access = free }}</ref> and B-Raf.<ref name="pmid15035987">{{cite journal | vauthors = Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R | title = Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF | journal = Cell | volume = 116 | issue = 6 | pages = 855–67 | date = March 2004 | pmid = 15035987 | doi = 10.1016/S0092-8674(04)00215-6 | s2cid = 126161 | doi-access = free }}</ref> It is highly similar to other Raf kinases and KSR proteins, and distinctly similar to some other MAP3 kinases, such as the Mixed Lineage Kinase (MLK) family. Together they comprise the Tyrosine Kinase Like (TKL) group of protein kinases. Although some features unite their catalytic domains with protein tyrosine kinases, the activity of TKLs is restricted to the phosphorylation of serine and threonine residues within target proteins. The most important substrate of Raf kinases (apart from itself) are the [[MAP2K1|MKK1]] and [[MAP2K2|MKK2]] kinases, whose activity strictly depends on phosphorylation events performed by Rafs.

==Evolutionary relationships==
{{Main|Raf kinase}}

Human c-Raf is a member of a larger family of related protein kinases. Two further members - found in most vertebrates - belong to the same family: [[BRAF (gene)|B-Raf]] and [[ARAF|A-Raf]]. Apart from the different length of their non-conserved N- and C-terminal ends, they all share the same domain architecture, structure and regulation. In comparison to the relatively well-known c-Raf and B-Raf, there is very little known of the precise function of A-Raf, but it is also thought to be similar to the other two members of the family. All these genes are believed to be the product of full gene or genome duplications at the dawn of vertebrate evolution, from a single ancestral Raf gene. Most other animal organisms possess only a single Raf gene. It is called Phl or Draf in Drosophila<ref name="pmid3037346">{{cite journal | vauthors = Mark GE, MacIntyre RJ, Digan ME, Ambrosio L, Perrimon N | title = Drosophila melanogaster homologs of the raf oncogene | journal = Mol. Cell. Biol. | volume = 7 | issue = 6 | pages = 2134–40 | date = June 1987 | pmid = 3037346 | pmc = 365335 | doi =  10.1128/mcb.7.6.2134}}</ref> and Lin-45 in C. elegans.<ref name="pmid12639709">{{cite journal | vauthors = Chong H, Vikis HG, Guan KL | title = Mechanisms of regulating the Raf kinase family | journal = Cell. Signal. | volume = 15 | issue = 5 | pages = 463–9 | date = May 2003 | pmid = 12639709 | doi = 10.1016/S0898-6568(02)00139-0 }}</ref>

[[File:Raf-kinases-and-relatives.png|thumb|left|upright=1.5|The family of Raf kinases (schematic architectures)]]
Multicellular animals also have a type of kinase closely related to Raf: this is the Kinase Suppressor of Ras (KSR). Vertebrates like mammals have two, [[Homology (biology)|paralogous]] KSR genes instead of one: [[KSR1]] and [[KSR2]]. Their C-terminal kinase domain is very similar to Raf (originally called CA5 in KSR and CR3 in Raf), but the N-terminal regulatory region differs. Although they also have the flexible hinge (CA4 in KSR) and a C1 domain (CA3 in KSR) before it, KSRs entirely lack the Ras-binding domain. Instead, they have unique regulatory regions on their N-termini, originally termed CA1 ("conserved area 1") and CA2. For a long time, the structure of the CA1 domain was a mystery. However, in 2012, the structure of the CA1 region in KSR1 was solved: it turned out to be a divergent [[Sterile alpha motif|SAM]] (sterile alpha motif) domain, supplemented with [[coiled coil|coiled-coils]] (CC-SAM): this is supposed to aid KSRs in membrane binding.<ref name="pmid23250398">{{cite journal | vauthors = Koveal D, Schuh-Nuhfer N, Ritt D, Page R, Morrison DK, Peti W | title = A CC-SAM, for coiled coil-sterile α motif, domain targets the scaffold KSR-1 to specific sites in the plasma membrane | journal = Sci Signal | volume = 5 | issue = 255 | pages = ra94 | date = December 2012 | pmid = 23250398 | doi = 10.1126/scisignal.2003289 | pmc=3740349}}</ref> KSRs, like Rafs, also have the twin 14-3-3 associating motifs (that depend on phosphorylation), but also possess novel MAPK-binding motifs on  their hinge regions. With a typical sequence Phe-x-Phe-Pro (FxFP) these motifs are important for the feedback regulation of Raf kinases in the [[MAPK/ERK pathway|ERK1/2 pathway]]. According to our current knowledge, KSRs also participate in the same pathway as Raf, although they only play an auxiliary role. With a very poor intrinsic kinase activity, they were long thought to be inactive, until their catalytic activity was finally demonstrated in recent years.<ref name="pmid21441104">{{cite journal | vauthors = Hu J, Yu H, Kornev AP, Zhao J, Filbert EL, Taylor SS, Shaw AS | title = Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 108 | issue = 15 | pages = 6067–72 | date = April 2011 | pmid = 21441104 | pmc = 3076888 | doi = 10.1073/pnas.1102554108 | bibcode = 2011PNAS..108.6067H | doi-access = free }}</ref><ref name="pmid21441910">{{cite journal | vauthors = Brennan DF, Dar AC, Hertz NT, Chao WC, Burlingame AL, Shokat KM, Barford D | title = A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK | journal = Nature | volume = 472 | issue = 7343 | pages = 366–9 | date = April 2011 | pmid = 21441910 | doi = 10.1038/nature09860 | bibcode = 2011Natur.472..366B | s2cid = 18818 }}</ref> But even then, they contribute only negligibly to [[MAP2K1|MKK1]] and [[MAP2K2|MKK2]] phosphorylation. The main role of KSR appears to be to provide a heterodimerization partner to Raf enzymes, greatly facilitating their activation by means of allostery. Similar phenomena  were described for other MAP3 kinases. ASK2, for example, is a poor enzyme on its own, and it activity appears to be tied to ASK1/ASK2 heterodimerisation.<ref name="pmid17714688">{{cite journal | vauthors = Ortner E, Moelling K | title = Heteromeric complex formation of ASK2 and ASK1 regulates stress-induced signaling | journal = Biochem. Biophys. Res. Commun. | volume = 362 | issue = 2 | pages = 454–9 | date = October 2007 | pmid = 17714688 | doi = 10.1016/j.bbrc.2007.08.006 }}</ref>

Raf-like kinases are fully absent from fungi. But recent sequencing of other [[opisthokont]]s (e.g. [[Capsaspora|Capsaspora owczarzaki]]) revealed the presence of genuine Raf kinases in unicellular eukaryotes. Therefore, it is possible that Raf proteins are an ancient heritage and ancestors of fungi secondarily lost Raf-dependent signaling. Fungal [[Mitogen-activated protein kinase|MAP kinase pathways]] that are homologous to the mammalian [[MAPK/ERK pathway|ERK1/2 pathway]] (Fus3 and Kss1 in yeast) are activated by MEKK-related kinases (e.g. Ste11 in yeast) instead of Raf enzymes.

Raf kinases found in retroviruses (such as murine v-Raf) are secondarily derived from the corresponding vertebrate genes of their hosts. These Raf genes encode severely truncated proteins, that lack the entire N-terminal autoinhibitory domain, and the 14-3-3 binding motifs. Such severe truncations are known to induce an uncontrolled activity of Raf kinases: that is just exactly what a virus may need for efficient reproduction.

==Regulation of activity==
[[File:C-Raf-14-3-3-complex.png|thumb|left|upright=1.5|Artist's impression of the autoinhibited state of c-Raf, reinforced by the associated 14-3-3 protein dimers, bound to the phosphorylated twin motifs.<ref name="pmid21779496">{{cite journal | vauthors = Matallanas D, Birtwistle M, Romano D, Zebisch A, Rauch J, von Kriegsheim A, Kolch W | title = Raf family kinases: old dogs have learned new tricks | journal = Genes Cancer | volume = 2 | issue = 3 | pages = 232–60 | year = 2011 | pmid = 21779496 | pmc = 3128629 | doi = 10.1177/1947601911407323 }}</ref><ref name="pmid20883493">{{cite journal | vauthors = Alexa A, Varga J, Reményi A | title = Scaffolds are 'active' regulators of signaling modules | journal = FEBS J. | volume = 277 | issue = 21 | pages = 4376–82 | year = 2010 | pmid = 20883493 | doi = 10.1111/j.1742-4658.2010.07867.x | s2cid = 43848866 | doi-access = free }}</ref>]]

As mentioned above, the regulation of c-Raf activity is complex. As a "gatekeeper" of the [[MAPK/ERK pathway|ERK1/2 pathway]], it is kept in check by a multitude of inhibitory mechanisms, and normally cannot be activated in a single step. The most important regulatory mechanism involves the direct, physical association of the N-terminal autoinhibitory block to the kinase domain of c-Raf. It results in the occlusion of the catalytic site and full shutdown of kinase activity.<ref name="pmid9689060" /> This "closed" state can only be relieved if the autoinhibitory domain of Raf engages a partner competing with its own kinase domain, most importantly GTP-bound Ras. Activated small G-proteins can thus break up the intramolecular interactions: this results in a conformational change ("opening") of c-Raf<ref name="pmid15711535">{{cite journal | vauthors = Terai K, Matsuda M | title = Ras binding opens c-Raf to expose the docking site for mitogen-activated protein kinase kinase | journal = EMBO Rep. | volume = 6 | issue = 3 | pages = 251–5 | date = March 2005 | pmid = 15711535 | pmc = 1299259 | doi = 10.1038/sj.embor.7400349 }}</ref> necessary for kinase activation and substrate binding.

[[14-3-3 protein]]s also contribute to the autoinhibition. As 14-3-3 proteins are all known to form constitutive dimers, their assemblies have two binding sites.<ref name="pmid7603574">{{cite journal | vauthors = Liu D, Bienkowska J, Petosa C, Collier RJ, Fu H, Liddington R | title = Crystal structure of the zeta isoform of the 14-3-3 protein | journal = Nature | volume = 376 | issue = 6536 | pages = 191–4 | date = July 1995 | pmid = 7603574 | doi = 10.1038/376191a0 | bibcode = 1995Natur.376..191L | s2cid = 4366970 }}</ref> Thus the dimer acts as a "molecular handcuff", locking their binding partners at a fixed distance and orientation. When the precisely positioned twin 14-3-3 binding motifs are engaged by a single 14-3-3 protein dimer (such as 14-3-3 zeta), they become locked into a conformation that promotes autoinhibition and does not allow the disengagement of the autoinhibitory and catalytic domains.<ref name="pmid19049963">{{cite journal | vauthors = Fischer A, Baljuls A, Reinders J, Nekhoroshkova E, Sibilski C, Metz R, Albert S, Rajalingam K, Hekman M, Rapp UR | title = Regulation of RAF activity by 14-3-3 proteins: RAF kinases associate functionally with both homo- and heterodimeric forms of 14-3-3 proteins | journal = J. Biol. Chem. | volume = 284 | issue = 5 | pages = 3183–94 | date = January 2009 | pmid = 19049963 | doi = 10.1074/jbc.M804795200 | doi-access = free }}</ref> This "lockdown" of c-Raf (and other Rafs as well as KSRs) is controlled by motif phosphorylation. Unphosphorylated 14-3-3 associating motifs do not bind their partners: they need to get phosphorylated on conserved serines (Ser 259 and Ser 621) first, by other protein kinases. The most important kinase implicated in this event is [[MAP3K7|TGF-beta activated kinase 1]] (TAK1), and the enzymes dedicated for removal of these phosphates are the [[protein phosphatase 1]] (PP1) and protein phosphatase 2A (PP2A) complexes.<ref name="pmid16630891">{{cite journal | vauthors = Rodriguez-Viciana P, Oses-Prieto J, Burlingame A, Fried M, McCormick F | title = A phosphatase holoenzyme {{sic|comprised |hide=y|of}} Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity | journal = Mol. Cell | volume = 22 | issue = 2 | pages = 217–30 | date = April 2006 | pmid = 16630891 | doi = 10.1016/j.molcel.2006.03.027 | doi-access = free }}</ref><ref name="pmid11494123">{{cite journal | vauthors = Jaumot M, Hancock JF | title = Protein phosphatases 1 and 2A promote Raf-1 activation by regulating 14-3-3 interactions | journal = Oncogene | volume = 20 | issue = 30 | pages = 3949–58 | date = July 2001 | pmid = 11494123 | doi = 10.1038/sj.onc.1204526 | s2cid = 8800975 | doi-access = free }}</ref>

Note that 14-3-3 binding of Raf enzymes is not necessarily inhibitory: once Raf is open and dimerizes, 14-3-3s can also bind in ''trans'', bridging two kinases and "handcuffing" them together to reinforce the dimer, instead of keeping them away from each other.<ref name="pmid9665134">{{cite journal | vauthors = Tzivion G, Luo Z, Avruch J | title = A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity | journal = Nature | volume = 394 | issue = 6688 | pages = 88–92 | date = July 1998 | pmid = 9665134 | doi = 10.1038/27938 | bibcode = 1998Natur.394...88T | s2cid = 204998340 }}</ref> Further modes of 14-3-3 interactions with c-Raf also exist, but their role is not well known.<ref name="pmid22922483">{{cite journal | vauthors = Molzan M, Ottmann C | title = Synergistic binding of the phosphorylated S233- and S259-binding sites of C-RAF to one 14-3-3ζ dimer | journal = J. Mol. Biol. | volume = 423 | issue = 4 | pages = 486–95 | date = November 2012 | pmid = 22922483 | doi = 10.1016/j.jmb.2012.08.009 }}</ref>

Dimerisation is another important mechanism for c-Raf activity regulation and required for Raf [[activation loop]] phosphorylation. Normally, only the "open" kinase domains participate in dimerisation. Unlike B-Raf, that readily forms homodimers with itself, c-Raf prefers heterodimerisation with either B-Raf or KSR1.{{citation needed|date=February 2019}} Homodimers and heterodimers all behave similarly.<ref name="pmid21441910" /> The B-Raf homodimer kinase domain structure clearly shows that the activation loops (that control the catalytic activity of all known protein kinases) are positioned in an active-like conformation in the dimer. This is due to an allosteric effect of the other molecule binding to the "back" side of the kinase; such dimers are symmetric and have two, partially active catalytic sites. At this stage, the activity of Raf kinases is low, and unstable.

[[File:Raf-activation-cycle-sketch.png|thumb|left|upright=1.5|The activation cycle of mammalian Raf proteins, exemplified by B-Raf (a greatly simplified overview, not showing all steps).<ref name="pmid21779496" /><ref name="pmid20883493" />]]

To achieve full activity and stabilize the active state, the activation loop of c-Raf needs to be phosphorylated. The only kinases currently known to perform this act are the Raf family kinases themselves. But some other kinases, such as PAK1 can phosphorylate other residues near the kinase domain of c-Raf: the precise role of these auxiliary kinases is unknown. In the context of c-Raf, both c-Raf and KSR1 are needed for the "transphosphorylation" step. Due to the architecture of the dimers, this phosphorylation can only take place in ''trans'' (i.e. one dimer phosphorylates another, in a four-membered transitional complex).<ref name="pmid22292131">{{cite journal | vauthors = McKay MM, Freeman AK, Morrison DK | title = Complexity in KSR function revealed by Raf inhibitor and KSR structure studies | journal = Small GTPases | volume = 2 | issue = 5 | pages = 276–281 | year = 2011 | pmid = 22292131 | pmc = 3265819 | doi = 10.4161/sgtp.2.5.17740 }}</ref>  By interacting with conserved Arg and Lys residues in the kinase domain, the phosphorylated activation loops shift conformation and become ordered, permanently locking the kinase domain into a fully active state until dephosphorylated. The phosphorylated activation loops also render the kinase insensitive to the presence of its autoinhibitory domain.<ref name="pmid12865432">{{cite journal | vauthors = Chong H, Guan KL | title = Regulation of Raf through phosphorylation and N terminus-C terminus interaction | journal = J. Biol. Chem. | volume = 278 | issue = 38 | pages = 36269–76 | date = September 2003 | pmid = 12865432 | doi = 10.1074/jbc.M212803200 | doi-access = free }}</ref> KSRs cannot undergo this last step as they miss any phosphorylatable residues in their activation loops. But once c-Raf is fully activated, there is no further need to do so: active Raf enzymes can now engage their substrates.<ref name="pmid21617065">{{cite journal | vauthors = Shi F, Lemmon MA | title = Biochemistry. KSR plays CRAF-ty | journal = Science | volume = 332 | issue = 6033 | pages = 1043–4 | date = May 2011 | pmid = 21617065 | doi = 10.1126/science.1208063 | bibcode = 2011Sci...332.1043S | s2cid = 38639290 }}</ref> Like most protein kinases, c-Raf has multiple substrates. [[Bcl-2-associated death promoter|BAD]] (Bcl2-atagonist of cell death) is directly phosphorylated by c-Raf,<ref name="pmid22096607">{{cite journal | vauthors = Ye DZ, Jin S, Zhuo Y, Field J | title = p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112 | journal = PLOS ONE | volume = 6 | issue = 11 | pages = e27637 | year = 2011 | pmid = 22096607 | pmc = 3214075 | doi = 10.1371/journal.pone.0027637 | editor1-last = Bauer | bibcode = 2011PLoSO...627637Y | editor1-first = Joseph Alan | doi-access = free }}</ref> along with several types of [[adenylate cyclase]]s,<ref name="pmid15385642">{{cite journal | vauthors = Ding Q, Gros R, Gray ID, Taussig R, Ferguson SS, Feldman RD | s2cid = 9876605 | title = Raf kinase activation of adenylyl cyclases: isoform-selective regulation | journal = Mol. Pharmacol. | volume = 66 | issue = 4 | pages = 921–8 | date = October 2004 | pmid = 15385642 | doi = 10.1124/mol.66.4.921 }}</ref> [[(myosin-light-chain) phosphatase|myosin phosphatase]] (MYPT),<ref name="pmid11719507">{{cite journal | vauthors = Broustas CG, Grammatikakis N, Eto M, Dent P, Brautigan DL, Kasid U | title = Phosphorylation of the myosin-binding subunit of myosin phosphatase by Raf-1 and inhibition of phosphatase activity | journal = J. Biol. Chem. | volume = 277 | issue = 4 | pages = 3053–9 | date = January 2002 | pmid = 11719507 | doi = 10.1074/jbc.M106343200 | doi-access = free }}</ref> [[troponin|cardiac muscle troponin T]] (TnTc),<ref name="pmid19381846">{{cite journal | vauthors = Pfleiderer P, Sumandea MP, Rybin VO, Wang C, Steinberg SF | title = Raf-1: a novel cardiac troponin T kinase | journal = J. Muscle Res. Cell. Motil. | volume = 30 | issue = 1–2 | pages = 67–72 | year = 2009 | pmid = 19381846 | pmc = 2893395 | doi = 10.1007/s10974-009-9176-y }}</ref> etc. The [[retinoblastoma protein]] (pRb) and [[Cdc25|Cdc25 phosphatase]] were also suggested as possible substrates.<ref name="pmid11950876">{{cite journal | vauthors = Hindley A, Kolch W | title = Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK)-independent functions of Raf kinases | journal = J. Cell Sci. | volume = 115 | issue = Pt 8 | pages = 1575–81 | date = April 2002 | doi = 10.1242/jcs.115.8.1575 | pmid = 11950876 }}</ref>

The most important targets of all Raf enzymes are [[MAP2K1|MKK1(MEK1)]] and [[MAP2K2|MKK2(MEK2)]]. Although the structure of the enzyme-substrate complex c-Raf:MKK1 is unknown, it can be precisely modelled after the KSR2:MKK1 complex.<ref name="pmid21441910" /> Here no actual catalysis takes place, but it is thought to be highly similar to the way Raf binds to its substrates. The main interaction interface is provided by the C-terminal lobes of both kinase domains; the large, disordered, proline-rich loop unique to [[MAP2K1|MKK1]] and [[MAP2K2|MKK2]] also plays an important role in its positioning to Raf (and KSR).<ref name="pmid7565670">{{cite journal | vauthors = Catling AD, Schaeffer HJ, Reuter CW, Reddy GR, Weber MJ | title = A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function | journal = Mol. Cell. Biol. | volume = 15 | issue = 10 | pages = 5214–25 | date = October 1995 | pmid = 7565670 | pmc = 230769 | doi =  10.1128/mcb.15.10.5214}}</ref> These MKKs become phosphorylated on at least two sites in their activation loops upon binding to Raf: this will activate them too. The targets of the kinase cascade are ERK1 and ERK2, that are selectively activated by MKK1 or MKK2. ERKs have numerous substrates in cells; they are also capable of translocating into the nucleus to activate nuclear transcription factors. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, cell migration, inhibition of apoptosis, and cell differentiation.

==Associated human diseases==

Hereditary gain-of-function mutations of c-Raf are implicated in some rare, but severe syndromes. Most of these mutations involve single amino acid changes at one of the two 14-3-3 binding motifs.<ref name="pmid17603483">{{cite journal | vauthors = Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD | title = Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy | journal = Nat. Genet. | volume = 39 | issue = 8 | pages = 1007–12 | date = August 2007 | pmid = 17603483 | doi = 10.1038/ng2073 | s2cid = 19335210 }}</ref><ref name="pmid20679480">{{cite journal | vauthors = Molzan M, Schumacher B, Ottmann C, Baljuls A, Polzien L, Weyand M, Thiel P, Rose R, Rose M, Kuhenne P, Kaiser M, Rapp UR, Kuhlmann J, Ottmann C | title = Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling | journal = Mol. Cell. Biol. | volume = 30 | issue = 19 | pages = 4698–711 | date = October 2010 | pmid = 20679480 | pmc = 2950525 | doi = 10.1128/MCB.01636-09 }}</ref> Mutation of c-Raf is one of the possible causes of [[Noonan syndrome]]: affected individuals have congenital heart defects, short and dysmorphic stature and several other deformities. Similar mutations in c-Raf can also cause a related condition, termed [[LEOPARD syndrome]] (Lentigo, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth, Deafness), with a complex association of defects.

==Role in cancer==

Although c-Raf is very clearly capable of mutating into an oncogene in experimental settings, and even in a few human tumors,<ref name="pmid8451761">{{cite journal | vauthors = Storm SM, Rapp UR | title = Oncogene activation: c-raf-1 gene mutations in experimental and naturally occurring tumors | journal = Toxicol. Lett. | volume = 67 | issue = 1–3 | pages = 201–10 | date = April 1993 | pmid = 8451761 | doi = 10.1016/0378-4274(93)90056-4 | url = https://zenodo.org/record/1258537 }}</ref><ref name="pmid16585161">{{cite journal | vauthors = Zebisch A, Staber PB, Delavar A, Bodner C, Hiden K, Fischereder K, Janakiraman M, Linkesch W, Auner HW, Emberger W, Windpassinger C, Schimek MG, Hoefler G, Troppmair J, Sill H | title = Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia | journal = Cancer Res. | volume = 66 | issue = 7 | pages = 3401–8 | date = April 2006 | pmid = 16585161 | doi = 10.1158/0008-5472.CAN-05-0115 | doi-access = free }}</ref> its sister kinase B-Raf is the true major player in carcinogenesis in humans.<ref name="pmid16266992">{{cite journal | vauthors = Emuss V, Garnett M, Mason C, Marais R | title = Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF | journal = Cancer Res. | volume = 65 | issue = 21 | pages = 9719–26 | date = November 2005 | pmid = 16266992 | doi = 10.1158/0008-5472.CAN-05-1683 | doi-access = free }}</ref>

===B-Raf mutations===
Approximately 20% of all examined human tumor samples display a mutated B-Raf gene.<ref name="pmid20952405">{{cite journal | vauthors = Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, Jia M, Shepherd R, Leung K, Menzies A, Teague JW, Campbell PJ, Stratton MR, Futreal PA | title = COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer | journal = Nucleic Acids Res. | volume = 39 | issue = Database issue | pages = D945–50 | date = January 2011 | pmid = 20952405 | pmc = 3013785 | doi = 10.1093/nar/gkq929 }}</ref> The overwhelming majority of these mutations involve the exchange of a single amino acid: Val 600 into Glu, and this aberrant gene product (BRAF-V600E) can be visualized by immunohistochemistry for clinical molecular diagnostics<ref name="pmid22012135">{{cite journal | vauthors = Capper D, Berghoff AS, Magerle M, Ilhan A, Wöhrer A, Hackl M, Pichler J, Pusch S, Meyer J, Habel A, Petzelbauer P, Birner P, von Deimling A, Preusser M | title = Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases | journal = Acta Neuropathol. | volume = 123 | issue = 2 | pages = 223–33 | year = 2012 | pmid = 22012135 | doi = 10.1007/s00401-011-0887-y | s2cid = 35623183 }}</ref><ref name="pmid21638088">{{cite journal | vauthors = Capper D, Preusser M, Habel A, Sahm F, Ackermann U, Schindler G, Pusch S, Mechtersheimer G, Zentgraf H, von Deimling A | title = Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody | journal = Acta Neuropathol. | volume = 122 | issue = 1 | pages = 11–9 | year = 2011 | pmid = 21638088 | doi = 10.1007/s00401-011-0841-z | s2cid = 25647782 }}</ref> The aberration can mimic the activation loop phosphorylation and - by jumping all control steps at normal activation - immediately render the kinase domain fully active.<ref name="pmid15710605">{{cite journal | vauthors = Tran NH, Wu X, Frost JA | title = B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms | journal = J. Biol. Chem. | volume = 280 | issue = 16 | pages = 16244–53 | date = April 2005 | pmid = 15710605 | doi = 10.1074/jbc.M501185200 | doi-access = free }}</ref> Since B-Raf can also activate itself by homodimerisation and c-Raf by heterodimerisation, this mutation has a catastrophic effect by turning the ERK1/2 pathway constitutively active, and driving an uncontrolled process of cell division.<ref name="pmid16364920">{{cite journal | vauthors = Garnett MJ, Rana S, Paterson H, Barford D, Marais R | title = Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization | journal = Mol. Cell | volume = 20 | issue = 6 | pages = 963–9 | date = December 2005 | pmid = 16364920 | doi = 10.1016/j.molcel.2005.10.022 | doi-access = free }}</ref>

==As a therapeutic target==

Due to the importance of both Ras and B-Raf mutations in tumorigenesis, several Raf inhibitors were developed to combat cancer, especially against B-Raf exhibiting the V600E mutation. [[Sorafenib]] was the first clinically useful agent, that provides a pharmacological alternative to treat previously largely untreatable malignancies, such as renal cell carcinoma and melanoma.<ref name="pmid21577205">{{cite journal | vauthors = Maurer G, Tarkowski B, Baccarini M | title = Raf kinases in cancer-roles and therapeutic opportunities | journal = Oncogene | volume = 30 | issue = 32 | pages = 3477–88 | date = August 2011 | pmid = 21577205 | doi = 10.1038/onc.2011.160 | doi-access = free }}</ref> Several other molecules followed up, such as [[Vemurafenib]], [[Regorafenib]], [[Dabrafenib]], etc.

Unfortunately, ATP-competitive [[B-Raf inhibitor]]s may have an undesired effect in K-Ras-dependent cancers: They are simply too selective for B-Raf. While they perfectly well inhibit B-Raf activity in case a mutant B-Raf is the primary culprit, they also promote homo- and heterodimerisation of B-Raf, with itself and c-Raf. This will actually ''enhance'' c-Raf activation instead of inhibiting it in case there is no mutation in any Raf genes, but their common upstream activator K-Ras protein is the one mutated.<ref name="pmid20130576" /> This "paradoxical" c-Raf activation necessitates the need to screen for B-Raf mutations in patients (by genetic diagnostics) before starting a B-Raf-inhibitor therapy.<ref name="pmid22553052">{{cite journal | vauthors = Kim DH, Sim T | title = Novel small molecule Raf kinase inhibitors for targeted cancer therapeutics | journal = Arch. Pharm. Res. | volume = 35 | issue = 4 | pages = 605–15 | date = March 2012 | pmid = 22553052 | doi = 10.1007/s12272-012-0403-5 | s2cid = 26714490 }}</ref>

== List of interacting proteins ==

C-Raf has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[AKT1]],<ref name = pmid10576742>{{cite journal | vauthors = Zimmermann S, Moelling K | title = Phosphorylation and regulation of Raf by Akt (protein kinase B) | journal = Science | volume = 286 | issue = 5445 | pages = 1741–4 | date = November 1999 | pmid = 10576742 | doi =  10.1126/science.286.5445.1741}}</ref> 
* [[ASK1]],<ref name = pmid11427728>{{cite journal | vauthors = Chen J, Fujii K, Zhang L, Roberts T, Fu H | title = Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 14 | pages = 7783–8 | date = July 2001 | pmid = 11427728 | pmc = 35419 | doi = 10.1073/pnas.141224398 |bibcode = 2001PNAS...98.7783C | doi-access = free }}</ref> 
* [[BAG1]],<ref name = pmid8692945>{{cite journal | vauthors = Wang HG, Takayama S, Rapp UR, Reed JC | title = Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 93 | issue = 14 | pages = 7063–8 | date = July 1996 | pmid = 8692945 | pmc = 38936 | doi =  10.1073/pnas.93.14.7063|bibcode = 1996PNAS...93.7063W | doi-access = free }}</ref> 
* [[BRAF (gene)|BRAF]],<ref name = pmid11325826>{{cite journal | vauthors = Weber CK, Slupsky JR, Kalmes HA, Rapp UR | title = Active Ras induces heterodimerization of cRaf and BRaf | journal = Cancer Res. | volume = 61 | issue = 9 | pages = 3595–8 | date = May 2001 | pmid = 11325826 }}</ref> 
* [[Bcl-2]],<ref name = pmid8929532>{{cite journal | vauthors = Wang HG, Rapp UR, Reed JC | title = Bcl-2 targets the protein kinase Raf-1 to mitochondria | journal = Cell | volume = 87 | issue = 4 | pages = 629–38 | date = November 1996 | pmid = 8929532 | doi =  10.1016/s0092-8674(00)81383-5| s2cid = 16559750 | doi-access = free }}</ref> 
* [[CDC25A]],<ref name = pmid7744247>{{cite journal | vauthors = Galaktionov K, Jessus C, Beach D | title = Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation | journal = Genes Dev. | volume = 9 | issue = 9 | pages = 1046–58 | date = May 1995 | pmid = 7744247 | doi =  10.1101/gad.9.9.1046| doi-access = free }}</ref><ref name = pmid9230211>{{cite journal | vauthors = Huang TS, Shu CH, Yang WK, Whang-Peng J | title = Activation of CDC 25 phosphatase and CDC 2 kinase involved in GL331-induced apoptosis | journal = Cancer Res. | volume = 57 | issue = 14 | pages = 2974–8 | date = July 1997 | pmid = 9230211 }}</ref> 
* [[CFLAR]],<ref name = pmid10837247>{{cite journal | vauthors = Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J | title = The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways | journal = Curr. Biol. | volume = 10 | issue = 11 | pages = 640–8 | date = June 2000 | pmid = 10837247 | doi =  10.1016/s0960-9822(00)00512-1| s2cid = 14819939 | doi-access = free | bibcode = 2000CBio...10..640K }}</ref> 
* [[FYN]],<ref name = pmid7517401/> 
* [[GRB10]],<ref name = pmid10585452>{{cite journal | vauthors = Nantel A, Huber M, Thomas DY | title = Localization of endogenous Grb10 to the mitochondria and its interaction with the mitochondrial-associated Raf-1 pool | journal = J. Biol. Chem. | volume = 274 | issue = 50 | pages = 35719–24 | date = December 1999 | pmid = 10585452 | doi =  10.1074/jbc.274.50.35719| doi-access = free }}</ref><ref name = pmid9553107>{{cite journal | vauthors = Nantel A, Mohammad-Ali K, Sherk J, Posner BI, Thomas DY | title = Interaction of the Grb10 adapter protein with the Raf1 and MEK1 kinases | journal = J. Biol. Chem. | volume = 273 | issue = 17 | pages = 10475–84 | date = April 1998 | pmid = 9553107 | doi =  10.1074/jbc.273.17.10475| doi-access = free }}</ref> 
* [[HRAS]],<ref name = pmid9154803>{{cite journal | vauthors = Stang S, Bottorff D, Stone JC | title = Interaction of activated Ras with Raf-1 alone may be sufficient for transformation of rat2 cells | journal = Mol. Cell. Biol. | volume = 17 | issue = 6 | pages = 3047–55 | date = June 1997 | pmid = 9154803 | pmc = 232157 | doi =  10.1128/MCB.17.6.3047}}</ref><ref name = pmid14654780>{{cite journal | vauthors = Germani A, Prabel A, Mourah S, Podgorniak MP, Di Carlo A, Ehrlich R, Gisselbrecht S, Varin-Blank N, Calvo F, Bruzzoni-Giovanelli H | title = SIAH-1 interacts with CtIP and promotes its degradation by the proteasome pathway | journal = Oncogene | volume = 22 | issue = 55 | pages = 8845–51 | date = December 2003 | pmid = 14654780 | doi = 10.1038/sj.onc.1206994 | doi-access = free }}</ref><ref name = pmid15031288>{{cite journal | vauthors = Mitin NY, Ramocki MB, Zullo AJ, Der CJ, Konieczny SF, Taparowsky EJ | title = Identification and characterization of rain, a novel Ras-interacting protein with a unique subcellular localization | journal = J. Biol. Chem. | volume = 279 | issue = 21 | pages = 22353–61 | date = May 2004 | pmid = 15031288 | doi = 10.1074/jbc.M312867200 | doi-access = free }}</ref><ref name = pmid14724584>{{cite journal | vauthors = Vargiu P, De Abajo R, Garcia-Ranea JA, Valencia A, Santisteban P, Crespo P, Bernal J | title = The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors | journal = Oncogene | volume = 23 | issue = 2 | pages = 559–68 | date = January 2004 | pmid = 14724584 | doi = 10.1038/sj.onc.1207161 | doi-access = free }}</ref><ref name = pmid12620389>{{cite journal | vauthors = Yuryev A, Wennogle LP | title = Novel raf kinase protein-protein interactions found by an exhaustive yeast two-hybrid analysis | journal = Genomics | volume = 81 | issue = 2 | pages = 112–25 | date = February 2003 | pmid = 12620389 | doi =  10.1016/s0888-7543(02)00008-3}}</ref><ref name = pmid10783161>{{cite journal | vauthors = Li W, Han M, Guan KL | title = The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf | journal = Genes Dev. | volume = 14 | issue = 8 | pages = 895–900 | date = April 2000 | doi = 10.1101/gad.14.8.895 | pmid = 10783161 | pmc = 316541 }}</ref><ref name = pmid10882715>{{cite journal | vauthors = Kiyono M, Kato J, Kataoka T, Kaziro Y, Satoh T | title = Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1 | journal = J. Biol. Chem. | volume = 275 | issue = 38 | pages = 29788–93 | date = September 2000 | pmid = 10882715 | doi = 10.1074/jbc.M001378200 | doi-access = free }}</ref><ref name = pmid9523700>{{cite journal | vauthors = Janoueix-Lerosey I, Pasheva E, de Tand MF, Tavitian A, de Gunzburg J | title = Identification of a specific effector of the small GTP-binding protein Rap2 | journal = Eur. J. Biochem. | volume = 252 | issue = 2 | pages = 290–8 | date = March 1998 | pmid = 9523700 | doi =  10.1046/j.1432-1327.1998.2520290.x| doi-access = free }}</ref><ref name = pmid10922060>{{cite journal | vauthors = Boettner B, Govek EE, Cross J, Van Aelst L | title = The junctional multidomain protein AF-6 is a binding partner of the Rap1A GTPase and associates with the actin cytoskeletal regulator profilin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 16 | pages = 9064–9 | date = August 2000 | pmid = 10922060 | pmc = 16822 | doi =  10.1073/pnas.97.16.9064|bibcode = 2000PNAS...97.9064B | doi-access = free }}</ref><ref name = pmid16803888>{{cite journal | vauthors = Karbowniczek M, Robertson GP, Henske EP | title = Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization | journal = J. Biol. Chem. | volume = 281 | issue = 35 | pages = 25447–56 | date = September 2006 | pmid = 16803888 | doi = 10.1074/jbc.M605273200 | doi-access = free }}</ref><ref name = pmid7862125>{{cite journal | vauthors = Han L, Colicelli J | title = A human protein selected for interference with Ras function interacts directly with Ras and competes with Raf1 | journal = Mol. Cell. Biol. | volume = 15 | issue = 3 | pages = 1318–23 | date = March 1995 | pmid = 7862125 | pmc = 230355 | doi =  10.1128/mcb.15.3.1318}}</ref><ref name = pmid7969158>{{cite journal | vauthors = Jelinek T, Catling AD, Reuter CW, Moodie SA, Wolfman A, Weber MJ | title = RAS and RAF-1 form a signalling complex with MEK-1 but not MEK-2 | journal = Mol. Cell. Biol. | volume = 14 | issue = 12 | pages = 8212–8 | date = December 1994 | pmid = 7969158 | pmc = 359360 | doi =  10.1128/mcb.14.12.8212}}</ref><ref name = pmid10369681>{{cite journal | vauthors = Romero F, Martínez-A C, Camonis J, Rebollo A | title = Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization | journal = EMBO J. | volume = 18 | issue = 12 | pages = 3419–30 | date = June 1999 | pmid = 10369681 | pmc = 1171421 | doi = 10.1093/emboj/18.12.3419 }}</ref><ref name = pmid8628317>{{cite journal | vauthors = Morcos P, Thapar N, Tusneem N, Stacey D, Tamanoi F | title = Identification of neurofibromin mutants that exhibit allele specificity or increased Ras affinity resulting in suppression of activated ras alleles | journal = Mol. Cell. Biol. | volume = 16 | issue = 5 | pages = 2496–503 | date = May 1996 | pmid = 8628317 | pmc = 231238 | doi =  10.1128/mcb.16.5.2496}}</ref><ref name = pmid8530446>{{cite journal | vauthors = Hu CD, Kariya K, Tamada M, Akasaka K, Shirouzu M, Yokoyama S, Kataoka T | title = Cysteine-rich region of Raf-1 interacts with activator domain of post-translationally modified Ha-Ras | journal = J. Biol. Chem. | volume = 270 | issue = 51 | pages = 30274–7 | date = December 1995 | pmid = 8530446 | doi =  10.1074/jbc.270.51.30274| doi-access = free }}</ref><ref name = pmid9150145>{{cite journal | vauthors = Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J | title = Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras | journal = Cell | volume = 89 | issue = 3 | pages = 457–67 | date = May 1997 | pmid = 9150145 | doi =  10.1016/s0092-8674(00)80226-3| s2cid = 14459536 | doi-access = free }}</ref><ref name = pmid12379659>{{cite journal | vauthors = Huang YZ, Zang M, Xiong WC, Luo Z, Mei L | title = Erbin suppresses the MAP kinase pathway | journal = J. Biol. Chem. | volume = 278 | issue = 2 | pages = 1108–14 | date = January 2003 | pmid = 12379659 | doi = 10.1074/jbc.M205413200 | doi-access = free }}</ref> 
* [[Heat shock protein 90kDa alpha (cytosolic), member A1|HSP90AA1]],<ref name = pmid19011619/><ref name = pmid8408024>{{cite journal | vauthors = Stancato LF, Chow YH, Hutchison KA, Perdew GH, Jove R, Pratt WB | title = Raf exists in a native heterocomplex with hsp90 and p50 that can be reconstituted in a cell-free system | journal = J. Biol. Chem. | volume = 268 | issue = 29 | pages = 21711–6 | date = October 1993 | doi = 10.1016/S0021-9258(20)80600-0 | pmid = 8408024 | doi-access = free }}</ref> 
* [[KRAS]],<ref name = pmid10783161/><ref name = pmid10882715/> 
* [[MAP2K1]],<ref name = pmid10757792/> 
* [[MAP3K1]],<ref name = pmid10969079>{{cite journal | vauthors = Karandikar M, Xu S, Cobb MH | title = MEKK1 binds raf-1 and the ERK2 cascade components | journal = J. Biol. Chem. | volume = 275 | issue = 51 | pages = 40120–7 | date = December 2000 | pmid = 10969079 | doi = 10.1074/jbc.M005926200 | doi-access = free }}</ref> 
* [[MAPK7]],<ref name = pmid10531364>{{cite journal | vauthors = English JM, Pearson G, Hockenberry T, Shivakumar L, White MA, Cobb MH | title = Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control | journal = J. Biol. Chem. | volume = 274 | issue = 44 | pages = 31588–92 | date = October 1999 | pmid = 10531364 | doi =  10.1074/jbc.274.44.31588| doi-access = free }}</ref> 
* [[MAPK8IP3]],<ref name = pmid11044439>{{cite journal | vauthors = Kuboki Y, Ito M, Takamatsu N, Yamamoto KI, Shiba T, Yoshioka K | title = A scaffold protein in the c-Jun NH2-terminal kinase signaling pathways suppresses the extracellular signal-regulated kinase signaling pathways | journal = J. Biol. Chem. | volume = 275 | issue = 51 | pages = 39815–8 | date = December 2000 | pmid = 11044439 | doi = 10.1074/jbc.C000403200 | doi-access = free }}</ref><ref name = pmid10523642>{{cite journal | vauthors = Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, Hibi M, Nakabeppu Y, Shiba T, Yamamoto KI | title = JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway | journal = Mol. Cell. Biol. | volume = 19 | issue = 11 | pages = 7539–48 | date = November 1999 | pmid = 10523642 | pmc = 84763 | doi =  10.1128/mcb.19.11.7539}}</ref> 
* [[PAK1]],<ref name = pmid11733498>{{cite journal | vauthors = Zang M, Hayne C, Luo Z | title = Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1 | journal = J. Biol. Chem. | volume = 277 | issue = 6 | pages = 4395–405 | date = February 2002 | pmid = 11733498 | doi = 10.1074/jbc.M110000200 | doi-access = free }}</ref> 
* [[Phosphatidylethanolamine binding protein 1|PEBP1]],<ref name = pmid10757792/> 
* [[Prohibitin|PHB]],<ref name = pmid10523633/> 
* [[Protein kinase Mζ|PRKCZ]],<ref name = pmid10620507/> 
* [[RAP1A]],<ref name = pmid7791872 /><ref name = pmid7862125/><ref name = pmid9867809>{{cite journal | vauthors = Hu CD, Kariya K, Okada T, Qi X, Song C, Kataoka T | title = Effect of phosphorylation on activities of Rap1A to interact with Raf-1 and to suppress Ras-dependent Raf-1 activation | journal = J. Biol. Chem. | volume = 274 | issue = 1 | pages = 48–51 | date = January 1999 | pmid = 9867809 | doi =  10.1074/jbc.274.1.48| doi-access = free }}</ref><ref name = pmid10454553>{{cite journal | vauthors = Okada T, Hu CD, Jin TG, Kariya K, Yamawaki-Kataoka Y, Kataoka T | title = The strength of interaction at the Raf cysteine-rich domain is a critical determinant of response of Raf to Ras family small GTPases | journal = Mol. Cell. Biol. | volume = 19 | issue = 9 | pages = 6057–64 | date = September 1999 | pmid = 10454553 | pmc = 84512 | doi =  10.1128/mcb.19.9.6057}}</ref> 
* [[RHEB]],<ref name = pmid15854902>{{cite journal | vauthors = Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J | title = Rheb binds and regulates the mTOR kinase | journal = Curr. Biol. | volume = 15 | issue = 8 | pages = 702–13 | date = April 2005 | pmid = 15854902 | doi = 10.1016/j.cub.2005.02.053 | s2cid = 3078706 | doi-access = free | bibcode = 2005CBio...15..702L }}</ref><ref name = pmid15150271>{{cite journal | vauthors = Karbowniczek M, Cash T, Cheung M, Robertson GP, Astrinidis A, Henske EP | title = Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent | journal = J. Biol. Chem. | volume = 279 | issue = 29 | pages = 29930–7 | date = July 2004 | pmid = 15150271 | doi = 10.1074/jbc.M402591200 | doi-access = free }}</ref><ref name = pmid9001246>{{cite journal | vauthors = Yee WM, Worley PF | title = Rheb interacts with Raf-1 kinase and may function to integrate growth factor- and protein kinase A-dependent signals | journal = Mol. Cell. Biol. | volume = 17 | issue = 2 | pages = 921–33 | date = February 1997 | pmid = 9001246 | pmc = 231818 | doi =  10.1128/mcb.17.2.921}}</ref> 
* [[RRAS2]]<ref name = pmid10783161/><ref name = pmid10557073>{{cite journal | vauthors = Movilla N, Crespo P, Bustelo XR | title = Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins | journal = Oncogene | volume = 18 | issue = 43 | pages = 5860–9 | date = October 1999 | pmid = 10557073 | doi = 10.1038/sj.onc.1202968 | doi-access = free }}</ref> 
* [[Retinoblastoma protein|RB1]],<ref name = pmid10523633>{{cite journal | vauthors = Wang S, Nath N, Fusaro G, Chellappan S | title = Rb and prohibitin target distinct regions of E2F1 for repression and respond to different upstream signals | journal = Mol. Cell. Biol. | volume = 19 | issue = 11 | pages = 7447–60 | date = November 1999 | pmid = 10523633 | pmc = 84738 | doi =  10.1128/mcb.19.11.7447}}</ref><ref name = pmid9819434/> 
* [[Retinoblastoma-like protein 2|RBL2]],<ref name = pmid9819434>{{cite journal | vauthors = Wang S, Ghosh RN, Chellappan SP | title = Raf-1 physically interacts with Rb and regulates its function: a link between mitogenic signaling and cell cycle regulation | journal = Mol. Cell. Biol. | volume = 18 | issue = 12 | pages = 7487–98 | date = December 1998 | pmid = 9819434 | pmc = 109329 | doi =  10.1128/mcb.18.12.7487}}</ref> 
* [[SHOC2]],<ref name = pmid10783161/>
* [[STUB1]],<ref name = pmid19011619>{{cite journal | vauthors = Dogan T, Harms GS, Hekman M, Karreman C, Oberoi TK, Alnemri ES, Rapp UR, Rajalingam K | title = X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility | journal = Nat. Cell Biol. | volume = 10 | issue = 12 | pages = 1447–55 | date = December 2008 | pmid = 19011619 | doi = 10.1038/ncb1804 | s2cid = 6553549 }}</ref> 
* [[Src (gene)|Src]],<ref name = pmid7517401>{{cite journal | vauthors = Cleghon V, Morrison DK | title = Raf-1 interacts with Fyn and Src in a non-phosphotyrosine-dependent manner | journal = J. Biol. Chem. | volume = 269 | issue = 26 | pages = 17749–55 | date = July 1994 | doi = 10.1016/S0021-9258(17)32504-8 | pmid = 7517401 | doi-access = free }}</ref> 
* [[TSC22D3]],<ref name = pmid12391160>{{cite journal | vauthors = Ayroldi E, Zollo O, Macchiarulo A, Di Marco B, Marchetti C, Riccardi C | title = Glucocorticoid-induced leucine zipper inhibits the Raf-extracellular signal-regulated kinase pathway by binding to Raf-1 | journal = Mol. Cell. Biol. | volume = 22 | issue = 22 | pages = 7929–41 | date = November 2002 | pmid = 12391160 | pmc = 134721 | doi =  10.1128/mcb.22.22.7929-7941.2002}}</ref> 
* [[YWHAB]],<ref name = pmid12620389/><ref name = pmid10620507/><ref name = pmid12360521>{{cite journal | vauthors = Truong AB, Masters SC, Yang H, Fu H | title = Role of the 14-3-3 C-terminal loop in ligand interaction | journal = Proteins | volume = 49 | issue = 3 | pages = 321–5 | date = November 2002 | pmid = 12360521 | doi = 10.1002/prot.10210 | s2cid = 31480274 }}</ref><ref name = pmid10848612>{{cite journal | vauthors = Yuryev A, Ono M, Goff SA, Macaluso F, Wennogle LP | title = Isoform-specific localization of A-RAF in mitochondria | journal = Mol. Cell. Biol. | volume = 20 | issue = 13 | pages = 4870–8 | date = July 2000 | pmid = 10848612 | pmc = 85938 | doi =  10.1128/mcb.20.13.4870-4878.2000}}</ref><ref name = pmid8702721>{{cite journal | vauthors = Vincenz C, Dixit VM | title = 14-3-3 proteins associate with A20 in an isoform-specific manner and function both as chaperone and adapter molecules | journal = J. Biol. Chem. | volume = 271 | issue = 33 | pages = 20029–34 | date = August 1996 | pmid = 8702721 | doi =  10.1074/jbc.271.33.20029| doi-access = free }}</ref><ref name = pmid7644510>{{cite journal | vauthors = Conklin DS, Galaktionov K, Beach D | title = 14-3-3 proteins associate with cdc25 phosphatases | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 17 | pages = 7892–6 | date = August 1995 | pmid = 7644510 | pmc = 41252 | doi =  10.1073/pnas.92.17.7892|bibcode = 1995PNAS...92.7892C | doi-access = free }}</ref> 
* [[YWHAE]],<ref name = pmid8702721/><ref name = pmid7644510/> 
* [[YWHAG]],<ref name = pmid10620507/><ref name = pmid17353931/><ref name = pmid10433554>{{cite journal | vauthors = Autieri MV, Carbone CJ | title = 14-3-3Gamma interacts with and is phosphorylated by multiple protein kinase C isoforms in PDGF-stimulated human vascular smooth muscle cells | journal = DNA Cell Biol. | volume = 18 | issue = 7 | pages = 555–64 | date = July 1999 | pmid = 10433554 | doi = 10.1089/104454999315105 }}</ref> 
* [[YWHAH]],<ref name = pmid10620507/><ref name = pmid8702721/><ref name = pmid11969417>{{cite journal | vauthors = Ichimura T, Wakamiya-Tsuruta A, Itagaki C, Taoka M, Hayano T, Natsume T, Isobe T | title = Phosphorylation-dependent interaction of kinesin light chain 2 and the 14-3-3 protein | journal = Biochemistry | volume = 41 | issue = 17 | pages = 5566–72 | date = April 2002 | pmid = 11969417 | doi =  10.1021/bi015946f}}</ref> 
* [[YWHAQ]],<ref name = pmid10757792>{{cite journal | vauthors = Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM, Kolch W | title = Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein | journal = Mol. Cell. Biol. | volume = 20 | issue = 9 | pages = 3079–85 | date = May 2000 | pmid = 10757792 | pmc = 85596 | doi =  10.1128/mcb.20.9.3079-3085.2000}}</ref><ref name = pmid10620507>{{cite journal | vauthors = Van Der Hoeven PC, Van Der Wal JC, Ruurs P, Van Dijk MC, Van Blitterswijk J | title = 14-3-3 isotypes facilitate coupling of protein kinase C-zeta to Raf-1: negative regulation by 14-3-3 phosphorylation | journal = Biochem. J. | volume = 345 | issue =  2| pages = 297–306 | date = January 2000 | pmid = 10620507 | pmc = 1220759 | doi =  10.1042/0264-6021:3450297}}</ref><ref name = pmid17353931>{{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Mol. Syst. Biol. | volume = 3 | issue =  1| pages = 89 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 | year=2007}}</ref><ref name = pmid8663231>{{cite journal | vauthors = Liu YC, Elly C, Yoshida H, Bonnefoy-Berard N, Altman A | title = Activation-modulated association of 14-3-3 proteins with Cbl in T cells | journal = J. Biol. Chem. | volume = 271 | issue = 24 | pages = 14591–5 | date = June 1996 | pmid = 8663231 | doi =  10.1074/jbc.271.24.14591| doi-access = free }}</ref>  and
* [[YWHAZ]].<ref name = pmid10620507/><ref name = pmid9261098>{{cite journal | vauthors = Clark GJ, Drugan JK, Rossman KL, Carpenter JW, Rogers-Graham K, Fu H, Der CJ, Campbell SL | title = 14-3-3 zeta negatively regulates raf-1 activity by interactions with the Raf-1 cysteine-rich domain | journal = J. Biol. Chem. | volume = 272 | issue = 34 | pages = 20990–3 | date = August 1997 | pmid = 9261098 | doi =  10.1074/jbc.272.34.20990| doi-access = free }}</ref><ref name = pmid10887173>{{cite journal | vauthors = Tzivion G, Luo ZJ, Avruch J | title = Calyculin A-induced vimentin phosphorylation sequesters 14-3-3 and displaces other 14-3-3 partners in vivo | journal = J. Biol. Chem. | volume = 275 | issue = 38 | pages = 29772–8 | date = September 2000 | pmid = 10887173 | doi = 10.1074/jbc.M001207200 | doi-access = free }}</ref><ref name = pmid7628630>{{cite journal | vauthors = Koyama S, Williams LT, Kikuchi A | title = Characterization of the interaction of Raf-1 with ras p21 or 14-3-3 protein in intact cells | journal = FEBS Lett. | volume = 368 | issue = 2 | pages = 321–5 | date = July 1995 | pmid = 7628630 | doi =  10.1016/0014-5793(95)00686-4| s2cid = 29625141 | doi-access = free }}</ref><ref name = pmid10611249>{{cite journal | vauthors = Chow CW, Davis RJ | title = Integration of calcium and cyclic AMP signaling pathways by 14-3-3 | journal = Mol. Cell. Biol. | volume = 20 | issue = 2 | pages = 702–12 | date = January 2000 | pmid = 10611249 | pmc = 85175 | doi =  10.1128/MCB.20.2.702-712.2000}}</ref> 
{{Div col end}}

== See also ==

*[[Raf kinase]]s
*[[ARAF|A-Raf kinase]]
*[[BRAF (gene)|B-Raf kinase]]
*[[KSR1|KSR1 protein]]
*[[KSR2|KSR2 protein]]

== References ==
{{reflist|35em}}

== Further reading ==
{{refbegin|35em}}
* {{cite book | vauthors = Reed JC, Zha H, Aime-Sempe C, Takayama S, Wang HG | chapter = Structure—Function Analysis of BCL-2 Family Proteins | title = Mechanisms of Lymphocyte Activation and Immune Regulation VI | series = Adv. Exp. Med. Biol. | date = 1996 | volume = 406 | pages = 99–112 | pmid = 8910675 | doi =  10.1007/978-1-4899-0274-0_10| isbn = 978-1-4899-0276-4 }}
* {{cite journal | vauthors = Geyer M, Fackler OT, Peterlin BM | title = Structure–function relationships in HIV-1 Nef | journal = EMBO Rep. | volume = 2 | issue = 7 | pages = 580–5 | year = 2001 | pmid = 11463741 | pmc = 1083955 | doi = 10.1093/embo-reports/kve141 }}
* {{cite journal | vauthors = Dhillon AS, Kolch W | title = Untying the regulation of the Raf-1 kinase | journal = Arch. Biochem. Biophys. | volume = 404 | issue = 1 | pages = 3–9 | year = 2002 | pmid = 12127063 | doi = 10.1016/S0003-9861(02)00244-8 }}
* {{cite journal | vauthors = Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M | title = HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication | journal = J. Biosci. | volume = 28 | issue = 3 | pages = 323–35 | year = 2004 | pmid = 12734410 | doi = 10.1007/BF02970151 | s2cid = 33749514 }}
* {{cite journal | vauthors = Chen H, Kunnimalaiyaan M, Van Gompel JJ | title = Medullary thyroid cancer: the functions of raf-1 and human achaete-scute homologue-1 | journal = Thyroid | volume = 15 | issue = 6 | pages = 511–21 | year = 2006 | pmid = 16029117 | doi = 10.1089/thy.2005.15.511 }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=noonan  GeneReviews/NCBI/NIH/UW entry on Noonan syndrome]
* Domain structure [http://www.ebi.ac.uk/interpro/ISpy?ipr=IPR003116&tax_id=9606 diagrams] for Raf-1, A-Raf and B-Raf.
* [http://www.sdbonline.org/fly/genebrief/raf.htm ''Drosophila'' ''pole hole'' - The Interactive Fly]
* {{MeshName|c-raf+Proteins}}
* {{UCSC gene info|RAF1}}
* {{PDBe-KB2|P04049|RAF proto-oncogene serine/threonine-protein kinase}}

{{PDB Gallery|geneid=5894}}
{{MAPK ERK signaling pathway}}
{{Oncogenes}}
{{Serine/threonine-specific protein kinases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

[[Category:Protein kinases]]
[[Category:EC 2.7.11]]