View source for Platelet-derived growth factor receptor

{{Short description|Cell surface receptors}}
{{More citations needed|date=November 2019}}
{{Pfam_box
| Symbol = PDGFR
| Name = Platelet-derived growth factor receptor
| image = PDGFR-beta 3MJG.png
| width =
| caption = Ribbon image of two molecules of human PDGF receptor beta (yellow and magenta) in complex with dimeric [[PDGFB|PDGF-B]] (cyan and green).<ref name="3MJG">{{PDB|3MJG}}; {{cite journal | vauthors = Shim AH, Liu H, Focia PJ, Chen X, Lin PC, He X | title = Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 25 | pages = 11307–12 | date = June 2010 | pmid = 20534510 | pmc = 2895058 | doi = 10.1073/pnas.1000806107 | bibcode = 2010PNAS..10711307H | doi-access = free }}; rendered using [http://pymol.sourceforge.net PyMOL].</ref>
| InterPro= IPR006782
| SMART=
| PROSITE = 
| SCOP = 
| TCDB = 
| OPM family= 
| OPM protein= 
| Pfam= PF04692
| PDB=
| Membranome family= 1204
}}
{{infobox protein
|Name= [[PDGFRA|platelet-derived growth factor receptor, alpha polypeptide]]
|caption=
|image=
|width=
|HGNCid=8803
|Symbol=[[PDGFRA]]
|AltSymbols=
|EntrezGene=5156
|OMIM=173490
|RefSeq=NM_006206
|UniProt=P16234
|PDB=
|ECnumber=
|Chromosome=4
|Arm=q
|Band=12
|LocusSupplementaryData=
}}
{{infobox protein
|Name=[[PDGFRB|platelet-derived growth factor receptor, beta polypeptide]]
|caption = 
|image = 
|width=
|HGNCid=8804
|Symbol=[[PDGFRB]]
|AltSymbols=PDGFR
|EntrezGene=5159
|OMIM=173410
|RefSeq=NM_002609
|UniProt=P09619
|PDB=
|ECnumber=
|Chromosome=5
|Arm=q
|Band=31
|LocusSupplementaryData=-q32
}}
'''Platelet-derived growth factor receptors''' ('''PDGF-R''') are cell surface [[receptor tyrosine kinase|tyrosine kinase receptor]]s for members of the [[platelet-derived growth factor]] (PDGF) family. PDGF subunits [[PDGFA|-A]] and [[PDGFB|-B]] are important factors regulating [[cell proliferation]], [[cellular differentiation]], [[cell growth]], [[Morphogenesis|development]] and many diseases including [[cancer]].<ref name="pmid2538922">{{cite journal | vauthors = Williams LT | title = Signal transduction by the platelet-derived growth factor receptor | journal = Science | volume = 243 | issue = 4898 | pages = 1564–70 | date = March 1989 | pmid = 2538922 | doi = 10.1126/science.2538922 | bibcode = 1989Sci...243.1564W }}</ref>  There are two forms of the PDGF-R, [[PDGFRA|alpha]] and [[PDGFRB|beta]] each encoded by a different gene.<ref name="pmid2543106">{{cite journal | vauthors = Heldin CH, Westermark B | title = Platelet-derived growth factor: three isoforms and two receptor types | journal = Trends in Genetics | volume = 5 | issue = 4 | pages = 108–11 | date = April 1989 | pmid = 2543106 | doi = 10.1016/0168-9525(89)90040-1 }}</ref>  Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.<ref name="pmid1315403">{{cite journal | vauthors = Heldin CH, Ostman A, Eriksson A, Siegbahn A, Claesson-Welsh L, Westermark B | title = Platelet-derived growth factor: isoform-specific signalling via heterodimeric or homodimeric receptor complexes | journal = Kidney International | volume = 41 | issue = 3 | pages = 571–4 | date = March 1992 | pmid = 1315403 | doi = 10.1038/ki.1992.84 | doi-access = free }}</ref>

==Mechanism of action==
The PDGF family consists of PDGF-A, -B, -C and -D, which form either homo- or hetero[[protein dimer|dimer]]s (PDGF-AA, -AB, -BB, -CC, -DD). The four PDGFs are inactive in their [[monomer]]ic forms. The PDGFs bind to the protein [[Receptor tyrosine kinase|tyrosine kinase receptor]]s PDGF receptor-α and -β. These two receptor [[isoform]]s [[protein dimer|dimer]]ize upon binding the PDGF dimer, leading to three possible receptor combinations, namely -αα, -ββ and -αβ. The [[extracellular]] region of the [[Receptor (biochemistry)|receptor]] consists of five [[immunoglobulin]]-like domains while the intracellular part is a [[tyrosine kinase]] domain. The ligand-binding sites of the receptors are located to the three first immunoglobulin-like domains. PDGF-CC specifically interacts with PDGFR-αα and -αβ, but not with -ββ, and thereby resembles PDGF-AB. PDGF-DD binds to PDGFR-ββ with high affinity, and to PDGFR-αβ to a markedly lower extent and is therefore regarded as PDGFR-ββ specific. PDGF-AA binds only to PDGFR-αα, while PDGF-BB is the only PDGF that can bind all three receptor combinations with high affinity.<ref name="pmid18392794">{{cite journal | vauthors = Cao Y, Cao R, Hedlund EM | title = R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways | journal = Journal of Molecular Medicine | volume = 86 | issue = 7 | pages = 785–9 | date = July 2008 | pmid = 18392794 | doi = 10.1007/s00109-008-0337-z | s2cid = 21872247 }}</ref>

Dimerization is a prerequisite for the [[activation]] of the [[kinase]]. Kinase activation is visualized as [[tyrosine]] [[phosphorylation]] of the receptor molecules, which occurs between the dimerized receptor molecules ([[transphosphorylation]]). In conjunction with dimerization and kinase activation, the receptor molecules undergo [[conformational change]]s, which allow a basal [[kinase]] activity to phosphorylate a critical [[tyrosine]] residue, thereby "unlocking" the kinase, leading to full [[enzyme|enzymatic]] activity directed toward other tyrosine residues in the receptor molecules as well as other [[Substrate (biochemistry)|substrate]]s for the kinase.
Expression of both receptors and each of the four PDGFs is under independent control, giving the PDGF/PDGFR system a high flexibility. Different cell types vary greatly in the ratio of PDGF isoforms and PDGFRs expressed. Different external stimuli such as [[inflammation]], [[embryonic development]] or differentiation modulate cellular receptor expression allowing binding of some PDGFs but not others. Additionally, some cells display only one of the PDGFR isoforms while other cells express both isoforms, simultaneously or separately.

==Interaction with signal transduction molecules==
Tyrosine phosphorylation sites in growth factor receptors serve two major purposes—to control the state of activity of the kinase and to create binding sites for downstream [[signal transduction]] molecules, which in many cases also are substrates for the kinase. The second part of the tyrosine kinase domain in the PDGFβ receptor is phosphorylated at Tyr-857, and mutant receptors carrying [[phenylalanine]] at this position have reduced kinase activity. Tyr-857 has therefore been assigned a role in positive regulation of kinase activity.<ref name="pmid2550144 ">{{cite journal | vauthors = Kazlauskas A, Cooper JA | title = Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins | journal = Cell | volume = 58 | issue = 6 | pages = 1121–33 | date = September 1989 | pmid = 2550144 | doi = 10.1016/0092-8674(89)90510-2 | s2cid = 25586248 }}</ref> Sites of tyrosine phosphorylation involved in binding signal transduction molecules have been identified in the [[wikt:juxtamembrane|juxtamembrane]] domain, the kinase insert, and in the [[C-terminal]] tail in the PDGFβ receptor. The phosphorylated tyrosine residue and in general three adjacent C-terminal amino acid residues form specific binding sites for signal transduction molecules. Binding to these sites involves a common conserved stretches, denoted the Src homology (SH) 2 domain and/or [[Phosphotyrosine]] Binding Domains (PTB). The specificity of these interactions appears to be very high, since mutant receptors carrying phenylalanine residues in one or several of the different phosphorylation sites generally lack the capacity to bind the targeted signal transduction molecule. The signal transduction molecules are either equipped with different enzymatic activities, or they are adaptor molecules, which in some but not all cases are found in complexes with subunits that carry a catalytic activity. Upon interaction with the activated receptor, the catalytic activities become up-regulated, through tyrosine phosphorylation or other mechanisms, generating a signal that may be unique for each type of signal transduction molecule.

Examination of the different [[Biochemical cascade|signaling cascade]]s induced by [[Receptor Tyrosine Kinase|RTK]]s established Ras/mitogen-activated protein kinase (MAPK), PI-3 kinase, and phospholipase-γ (PLCγ) pathways as key downstream mediators of PDGFR signaling.<ref name="pmid7682895">{{cite journal | vauthors = Valius M, Kazlauskas A | title = Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal | journal = Cell | volume = 73 | issue = 2 | pages = 321–34 | date = April 1993 | pmid = 7682895 | doi = 10.1016/0092-8674(93)90232-F | s2cid = 36305139 }}</ref><ref name="pmid9405485">{{cite journal | vauthors = Montmayeur JP, Valius M, Vandenheede J, Kazlauskas A | title = The platelet-derived growth factor beta receptor triggers multiple cytoplasmic signaling cascades that arrive at the nucleus as distinguishable inputs | journal = The Journal of Biological Chemistry | volume = 272 | issue = 51 | pages = 32670–8 | date = December 1997 | pmid = 9405485 | doi = 10.1074/jbc.272.51.32670 | doi-access = free }}</ref> In addition, [[reactive oxygen species]] (ROS)-dependent [[STAT3]] activation has been established to be a key downstream mediator of PDGFR signaling in vascular smooth muscle cells.<ref name="pmid24165129">{{cite journal | vauthors = Blazevic T, Schwaiberger AV, Schreiner CE, Schachner D, Schaible AM, Grojer CS, Atanasov AG, Werz O, Dirsch VM, Heiss EH | title = 12/15-lipoxygenase contributes to platelet-derived growth factor-induced activation of signal transducer and activator of transcription 3 | journal = The Journal of Biological Chemistry | volume = 288 | issue = 49 | pages = 35592–603 | date = December 2013 | pmid = 24165129 | pmc = 3853304 | doi = 10.1074/jbc.M113.489013 | doi-access = free }}</ref>

===MAPK pathway===
The adaptor protein Grb2 forms a complex with Sos by the Grb2 [[SH3 domain]].  Grb2 (or the Grb2/Sos complex) is recruited to the membrane by the Grb2 SH2 domain binding to activated PDGFR-bound SHP2 (also known as [[PTPN11]], a cytosolic [[Protein tyrosine phosphatase|PTP]]), thereby allowing interaction with Ras and the exchange of [[Guanosine diphosphate|GDP]] for [[Guanosine triphosphate|GTP]] on [[Ras subfamily|Ras]].  Whereas the interaction between Grb2 and PDGFR occurs through interaction with the SHP2 protein, Grb2 instead binds to activated EGFR through [[SHC1|Shc]], another adaptor protein that forms a complex with many receptors via its [[PTB domain]].<ref name="PMID 8193536">Schlessinger, J. SH2/SH3 Signaling Proteins. ''Curr. Op. Gen. Dev.'' 1994, '''4'''(1):25-30.</ref>  Once activated, Ras interacts with several proteins, namely Raf. Activated Raf stimulates MAPK-kinase (MAPKK or MEK) by phosphorylating a [[serine]] residue in its [[activation loop]]. [[MAPKK]] then phosphorylates MAPK (ERK1/2) on T and Y residues at the activation-loop leading to its activation. Activated MAPK phosphorylates a variety of cytoplasmic substrates, as well as transcription factors, when translocated into the nucleus. MAPK family members have been found to regulate various biological functions by phosphorylation of particular target molecules (such as transcription factors, other kinases etc.) located in cell membrane, [[cytoplasm]] and nucleus, and thus contribute to the regulation of different cellular processes such as cell proliferation, differentiation, [[apoptosis]] and [[immunoresponse]]s.

===PI3K pathway===
The class IA phospholipid kinase, PI-3 kinase, is activated by the majority of RTKs. Similarly to other SH2 domain-containing proteins, PI-3 kinase forms a complex with PY sites on activated receptors. The main function of [[PI3K]] activation is the generation of PIP3, which functions as a second messenger to activate downstream tyrosine kinases Btk and Itk, the Ser/Thr kinases PDK1 and [[Akt]] (PKB). The major biological functions of Akt activation can be classified into three categories – survival, proliferation and cell growth. Akt is also known to be implicated in several cancers, particularly breast. PLCγ is immediately recruited by an activated RTK through the binding of its SH2 domains to [[phosphotyrosine]] sites of the receptor. After activation, PLCγ hydrolyses its substrate PtdIns(4,5)P2 and forms two second messengers, diacylglycerol and Ins(1,4,5)P3. Ins(1,4,5)P3 stimulates the release of Ca 2+ from intracellular supplies. Ca 2+ then binds to calmodulin, which subsequently activates a family of calmodulindependent protein kinases (CamKs). In addition, both diacylglycerol and Ca 2+ activate members of the PKC family. The second messengers generated by PtdIns(4,5)P2 hydrolysis stimulate a variety of intracellular processes such as proliferation, angiogenesis, cell motility.

== See also ==
* [[Receptor tyrosine kinase]]
* [[PDGF]]
* [[Imatinib]]
* [[PDGFRA]]
* [[PDGFRB]]
* [[Crenolanib]] (CP-868,596-26)

== References ==
{{Reflist|32em}}

== External links ==
* {{MeshName|Platelet-Derived+Growth+Factor+Receptors}}

{{Growth factor receptors}}
{{Tyrosine kinases}}
{{Enzymes}}
{{Growth factor receptor modulators}}
{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:Platelet-Derived Growth Factor Receptor}}
[[Category:Growth factors]]
[[Category:Signal transduction]]
[[Category:Tyrosine kinase receptors]]