View source for Hedgehog signaling pathway

{{Short description|Embryonic signaling pathway for proper cell differentiation}}
{{Use dmy dates|date=April 2017}}
{{Infobox nonhuman protein
|UniProt=Q02936
|Symbol=hh
|Name=Protein hedgehog
|Organism=Drosophila melanogaster
}}
{{Pfam box
|Name=Hedge N-terminal signal
|Pfam=PF01085
|Symbol=HH_signal
|InterPro=IPR000320
|SCOP=3d1m
|CATH=3d1m
|below=See also {{InterPro|IPR001657}}.
}}
The '''Hedgehog signaling pathway''' is a [[signaling pathway]] that transmits information to [[embryo]]nic cells required for proper [[cell differentiation]]. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include [[cancer]].<ref name="BCDHedgehogAML">{{cite journal | vauthors = Jamieson C, Martinelli G, Papayannidis C, Cortes JE | title = Hedgehog Pathway Inhibitors: A New Therapeutic Class for the Treatment of Acute Myeloid Leukemia | journal = Blood Cancer Discovery | volume = 1 | issue = 2 | pages = 134–145 | date = September 2020 | pmid = 34661144 | pmc = 8447269 | doi = 10.1158/2643-3230.BCD-20-0007 | doi-access = free }}</ref><ref>{{cite web | vauthors = Kimball JW | date = 18 February 2008 | url = http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.html#hedgehog | title = The Hedgehog Signaling Pathway | work = Kimball's Biology Pages | archive-url = https://web.archive.org/web/20080626160057/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.html#hedgehog | archive-date = 26 June 2008 }}</ref>

The Hedgehog signaling pathway is one of the key regulators of animal development and is present in all [[bilateria]]ns.<ref name="Doinrg">{{cite journal | vauthors = Ingham PW, Nakano Y, Seger C | title = Mechanisms and functions of Hedgehog signalling across the metazoa | journal = Nature Reviews. Genetics | volume = 12 | issue = 6 | pages = 393–406 | date = June 2011 | pmid = 21502959 | doi = 10.1038/nrg2984 | s2cid = 33769324 }}</ref> The pathway takes its name from its [[polypeptide]] [[ligand (biochemistry)|ligand]], an intracellular signaling molecule called Hedgehog (''Hh'') found in fruit flies of the genus ''[[Drosophila]]''; fruit fly larvae lacking the ''Hh'' gene are said to resemble [[hedgehog]]s. ''Hh'' is one of Drosophila's [[segment polarity gene]] products, involved in establishing the basis of the fly [[body plan]]. The molecule remains important during later stages of [[embryogenesis]] and [[Metamorphosis (biology)|metamorphosis]].

Mammals have three Hedgehog homologues, [[Desert hedgehog (protein)|Desert (DHH)]], [[Indian hedgehog (protein)|Indian (IHH)]], and [[Sonic hedgehog|Sonic (SHH)]], of which Sonic is the best studied. The pathway is equally important during vertebrate embryonic development and is therefore of interest in [[evolutionary developmental biology]]. In [[knockout mice]] lacking components of the pathway, the [[brain]], [[skeleton]], [[musculature]], [[gastrointestinal tract]] and [[lungs]] fail to develop correctly. Recent studies point to the role of Hedgehog signaling in regulating [[adult stem cell]]s involved in maintenance and regeneration of adult [[biological tissue|tissues]]. The pathway has also been implicated in the development of some [[cancer]]s.<ref name=BCDHedgehogAML/> Drugs that specifically target Hedgehog signaling to fight this disease are being actively developed by a number of [[pharmaceutical company|pharmaceutical companies]].

==Discovery==
[[Image:Denticlebands.png|thumb|right|'''Figure 1.''' Normal and Hedgehog mutant larvae.]]
In the 1970s, a fundamental problem in [[developmental biology]] was to understand how a relatively simple egg can give rise to a complex [[Segmentation (biology)|segmented]] body plan. In the late 1970s [[Christiane Nüsslein-Volhard]] and [[Eric Wieschaus]] isolated mutations in genes that control development of the segmented anterior-posterior body axis of the fly;<ref name="NVW1980">{{cite journal | vauthors = Nüsslein-Volhard C, Wieschaus E | title = Mutations affecting segment number and polarity in Drosophila | journal = Nature | volume = 287 | issue = 5785 | pages = 795–801 | date = October 1980 | pmid = 6776413 | doi = 10.1038/287795a0 | s2cid = 4337658 | bibcode = 1980Natur.287..795N }}</ref> their "saturation mutagenesis" technique resulted in the discovery of a group of genes involved in the development of [[Morphogenesis#Anterior posterior axis patterning in Drosophila|body segmentation]], helping to found the field of [[evolutionary developmental biology]].<ref>{{cite journal | vauthors = Arthur W | title = The emerging conceptual framework of evolutionary developmental biology | journal = Nature | volume = 415 | issue = 6873 | pages = 757–764 | date = February 2002 | pmid = 11845200 | doi = 10.1038/415757a | s2cid = 4432164 | bibcode = 2002Natur.415..757A }}</ref> In 1995, they shared the [[Nobel Prize in Physiology or Medicine|Nobel Prize]] with [[Edward B. Lewis]] for their work studying genetic mutations in [[Drosophila embryogenesis|''Drosophila'' embryogenesis]].<ref name="Nobel">1995 Nobel Prize for discovery of [http://nobelprize.org/nobel_prizes/medicine/laureates/1995/press.html the genetic control of early embryonic development]</ref>

The ''Drosophila'' hedgehog (''hh'') gene was identified as one of several genes important for creating the differences between the anterior and posterior parts of individual body segments. The fly ''hh'' gene was independently cloned in 1992 by the labs of Jym Mohler, [[Philip Beachy]], [[Thomas B. Kornberg]] and Saigo Kaoru. Some hedgehog mutants result in abnormally-shaped embryos that are unusually short and stubby compared to [[wild type]] embryos. The function of the hedgehog segment polarity gene has been studied for influence on the normally polarized distribution of larval cuticular [[Dermal denticle|denticles]] as well as features on adult appendages such as legs and antennae.<ref name="Mohler">{{cite journal | vauthors = Mohler J | title = Requirements for hedgehog, a segmental polarity gene, in patterning larval and adult cuticle of Drosophila | journal = Genetics | volume = 120 | issue = 4 | pages = 1061–1072 | date = December 1988 | pmid = 3147217 | pmc = 1203569 | doi = 10.1093/genetics/120.4.1061 }}</ref> Rather than the normal pattern of denticles, hedgehog mutant larvae tend to have "solid lawns" of denticles (Figure 1). The appearance of the stubby and "hairy" larvae inspired the name '[[hedgehog]]'.

==Fruit fly==
[[File:HedgehogCiR.svg|thumb|left|'''Figure 2'''. Production of the CiR transcriptional repressor when Hh is not bound to [[PTCH1|Patched]]. In the diagram, "P" represents [[phosphate]].]]
[[File:HedgehogActive.svg|thumb|right|'''Figure 3'''. When Hh is bound to Patched (PTCH), Ci protein is able to act as a transcription factor in the nucleus.]]

===Mechanism===
Insect cells express a full size [[zinc-finger]] [[transcription factor]] [[Cubitus interruptus]] (Ci), which forms a complex with the [[kinesin]]-like protein Costal-2 (Cos2) and is localized in the cytoplasm bound to cellular [[microtubule]]s (Figure 2). The [[SCF complex]] targets the 155 kDa full length Ci protein for [[proteosome]]-dependent cleavage, which generates a 75 kDa fragment (CiR). CiR builds up in the cell and [[diffusion|diffuses]] into the [[cell nucleus|nucleus]], where it acts as a co-[[repressor]] for Hedgehog (''Hh'') target genes.<ref name="Collins2005">{{cite journal | vauthors = Collins RT, Cohen SM | title = A genetic screen in Drosophila for identifying novel components of the hedgehog signaling pathway | journal = Genetics | volume = 170 | issue = 1 | pages = 173–184 | date = May 2005 | pmid = 15744048 | pmc = 1449730 | doi = 10.1534/genetics.104.039420 }}</ref> The steps leading to Ci protein [[proteolysis]] include [[phosphorylation]] of Ci protein by several [[protein kinase]]s; [[CAMP-dependent protein kinase|PKA]], [[GSK-3|GSK3β]] and [[Casein kinase 1|CK1]] (Figure 2).<ref name="Lum">{{cite journal | vauthors = Lum L, Beachy PA | title = The Hedgehog response network: sensors, switches, and routers | journal = Science | volume = 304 | issue = 5678 | pages = 1755–1759 | date = June 2004 | pmid = 15205520 | doi = 10.1126/science.1098020 | s2cid = 13949436 | citeseerx = 10.1.1.476.3902 | bibcode = 2004Sci...304.1755L }}</ref> The ''Drosophila'' protein Slimb is part of an [[SCF complex]] that targets proteins for [[Ubiquitin|ubiquitylation]]. Slimb binds to [[phosphorylated]] Ci protein.

In the absence of Hh (Figure 3), a cell-surface transmembrane protein called [[PTCH1|Patched]] (PTCH) acts to prevent high expression and activity of a [[7TM Receptor|7 membrane spanning receptor]]<ref name="Chen">{{cite journal | vauthors = Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, de Sauvage F, Lefkowitz RJ | display-authors = 6 | title = Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2 | journal = Science | volume = 306 | issue = 5705 | pages = 2257–2260 | date = December 2004 | pmid = 15618519 | doi = 10.1126/science.1104135 | s2cid = 12823611 | bibcode = 2004Sci...306.2257C }}</ref> called [[Smoothened]] (SMO). Patched has sequence similarity to known membrane transport proteins. When extracellular Hh is present (Figure 3), it binds to and inhibits Patched, allowing Smoothened to accumulate and inhibit the proteolytic cleavage of the Ci protein. This process most likely involves the direct interaction of Smoothened and Costal-2 and may involve sequestration of the Ci protein-containing complex to a microdomain where the steps leading to Ci protein proteolysis are disrupted.<ref name="Collins2005" /> The mechanism by which Hh binding to Patched leads to increased levels of Smoothened is not clear (Step 1 in Figure 3). Following binding of Hh to Patched, Smoothened levels increase greatly over the level maintained in cells when Patched is not bound to Hh.<ref name="Alcedo2000">{{cite journal | vauthors = Alcedo J, Zou Y, Noll M | title = Posttranscriptional regulation of smoothened is part of a self-correcting mechanism in the Hedgehog signaling system | journal = Molecular Cell | volume = 6 | issue = 2 | pages = 457–465 | date = August 2000 | pmid = 10983991 | doi = 10.1016/S1097-2765(00)00044-7 | doi-access = free }}</ref> It has been suggested that phosphorylation of Smoothened plays a role in Hh-dependent regulation of Smoothened levels.<ref name="Apionishev ">{{cite journal | vauthors = Apionishev S, Katanayeva NM, Marks SA, Kalderon D, Tomlinson A | title = Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction | journal = Nature Cell Biology | volume = 7 | issue = 1 | pages = 86–92 | date = January 2005 | pmid = 15592457 | doi = 10.1038/ncb1210 | s2cid = 5958856 }}</ref>

In cells with Hh-activated Patched (Figure 3), the intact Ci protein accumulates in the cell cytoplasm and levels of CiR decrease, allowing transcription of some genes such as [[decapentaplegic]] (dpp, a member of the [[Bone morphogenetic protein|BMP]] growth factor family). For other Hh-regulated genes, expression requires not only the loss of CiR but also the positive action of uncleaved Ci to act as a [[transcriptional activator]].<ref name="Lum" /> Costal-2 is normally important for holding Ci protein in the cytoplasm, but interaction of Smoothened with Costal-2 allows some intact Ci protein to go to the nucleus. The ''Drosophila'' protein Fused (Fu in Figure 3) is a protein kinase that binds to Costal-2. Fused can inhibit Suppressor of Fused (SUFU), which in turn interacts with Ci to regulate gene transcription in some cell types.<ref name="Ho2005">{{cite journal | vauthors = Ho KS, Suyama K, Fish M, Scott MP | title = Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused | journal = Development | volume = 132 | issue = 6 | pages = 1401–1412 | date = March 2005 | pmid = 15750186 | doi = 10.1242/dev.01689 | doi-access = free }}</ref>

===Role===
[[File:Wingless and Hedgehog reciprocal signaling during segmentation of Drosophila embryos.svg|thumb|right|'''Figure 4.''' Interactions between [[Wnt signaling pathway|Wingless]] and Hedgehog]]

Hedgehog has roles in larval body segment development and in formation of adult appendages. During the formation of body segments in the developing ''Drosophila'' embryo, stripes of cells that synthesize the [[transcription factor]] [[engrailed (gene)|engrailed]] can also express the cell-to-cell signaling protein Hedgehog (green in Figure 4). Hedgehog is not free to move very far from the cells that make it and so it only activates a thin stripe of cells adjacent to the engrailed-expressing cells. When acting in this local fashion, hedgehog works as a [[paracrine signalling|paracrine]] factor. Only cells to one side of the engrailed-expressing cells are competent to respond to Hedgehog following interaction of Hh with the receptor protein Patched (blue in Figure 4).

Cells with Hh-activated Patched receptor synthesize the [[Wnt signaling pathway|Wingless]] protein (red in Figure 4). If a ''Drosophila'' embryo is altered so as to produce Hh in all cells, all of the competent cells respond and form a broader band of Wingless-expressing cells in each segment. The ''wingless'' gene has an upstream transcription regulatory region that binds the Ci transcription factor in a Hh-dependent fashion resulting in an increase in ''wingless'' transcription (interaction 2 in Figure 3) in a stripe of cells adjacent to the stripe of Hh-producing cells.<ref name="VonOhlen">{{cite journal | vauthors = Von Ohlen T, Lessing D, Nusse R, Hooper JE | title = Hedgehog signaling regulates transcription through cubitus interruptus, a sequence-specific DNA binding protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 6 | pages = 2404–2409 | date = March 1997 | pmid = 9122207 | pmc = 20100 | doi = 10.1073/pnas.94.6.2404 | doi-access = free | bibcode = 1997PNAS...94.2404V }}</ref>

Wingless protein acts as an extracellular signal and patterns the adjacent rows of cells by activating its cell surface receptor [[Frizzled]]. Wingless acts on engrailed-expressing cells to stabilize the stripes of engrailed expression. Wingless is a member of the [[Wnt signaling pathway|Wnt]] family of cell-to-cell signaling proteins. The reciprocal signaling by Hedgehog and Wingless stabilizes the boundary between parasegments (Figure 4, top). The effects of Wingless and Hedgehog on other stripes of cells in each segment establishes a positional code that accounts for the distinct anatomical features along the anterior-posterior axis of the segments.<ref name="Ingham2001">{{cite journal | vauthors = Ingham PW, McMahon AP | title = Hedgehog signaling in animal development: paradigms and principles | journal = Genes & Development | volume = 15 | issue = 23 | pages = 3059–3087 | date = December 2001 | pmid = 11731473 | doi = 10.1101/gad.938601 | doi-access = free }}</ref>

The Wingless protein is called "wingless" because of the [[phenotype]] of some ''wingless'' fly mutants. Wingless and Hedgehog function together during [[Metamorphosis (biology)|metamorphosis]] to coordinate wing formation. Hedgehog is expressed in the posterior part of developing ''Drosophila'' limbs. Hedgehog also participates in the coordination of eye, brain, gonad, gut and tracheal development. Downregulation of hedgehog has been implicated in reduced eye development in the amphipod ''[[Gammarus|Gammarus minus]]''.<ref>{{cite journal | vauthors = Aspiras AC, Prasad R, Fong DW, Carlini DB, Angelini DR | title = Parallel reduction in expression of the eye development gene hedgehog in separately derived cave populations of the amphipod Gammarus minus | journal = Journal of Evolutionary Biology | volume = 25 | issue = 5 | pages = 995–1001 | date = May 2012 | pmid = 22462461 | doi = 10.1111/j.1420-9101.2012.02481.x | s2cid = 37541721 }}</ref>

== Annelids ==
''Hedgehog'' is also involved in segmentation in the annelid worms; because [[parallel evolution]] seems unlikely, this suggests a common origin of segmentation between the two phyla.<ref name=Dray2010>{{cite journal | vauthors = Dray N, Tessmar-Raible K, Le Gouar M, Vibert L, Christodoulou F, Schipany K, Guillou A, Zantke J, Snyman H, Béhague J, Vervoort M, Arendt D, Balavoine G | display-authors = 6 | title = Hedgehog signaling regulates segment formation in the annelid Platynereis | journal = Science | volume = 329 | issue = 5989 | pages = 339–342 | date = July 2010 | pmid = 20647470 | pmc = 3182550 | doi = 10.1126/science.1188913 | bibcode = 2010Sci...329..339D }}</ref> Whilst Hh does not induce the formation of segments, it seems to act to stabilize the segmented fields once they have appeared.<ref name=Dray2010/>

==Vertebrates==
===Mechanism===
[[File:Sonic hedgehog pathway.svg|thumb|right|300px|'''Figure 5.''' Overview of [[Sonic hedgehog protein|Sonic hedgehog]] signaling.]]

[[Sonic hedgehog protein|Sonic hedgehog]] (SHH) is the best studied ligand of the vertebrate pathway. Most of what is known about hedgehog signaling has been established by studying SHH. It is [[translation (genetics)|translated]] as a ~45kDa precursor and undergoes [[autocatalytic]] processing (Process "1" on Figure 5) to produce an ~20kDa [[N-terminal]] signaling domain (referred to as SHH-N) and a ~25kDa [[C-terminal]] domain with no known signaling role. During the cleavage, a [[cholesterol]] molecule is added to the [[carboxyl]] end of the N-terminal domain,<ref>{{cite journal | vauthors = Banavali NK | title = The Mechanism of Cholesterol Modification of Hedgehog Ligand | journal = Journal of Computational Chemistry | volume = 41 | issue = 6 | pages = 520–527 | date = March 2020 | pmid = 31823413 | doi = 10.1002/jcc.26097 | doi-access = free }}</ref> which is involved in trafficking, secretion and receptor interaction of the ligand. SHH can signal in an [[autocrine]] fashion, affecting the cells in which it is produced. [[Secretion]] and consequent [[paracrine]] hedgehog signaling require the participation of Dispatched (DISP) protein (Process "2" on Figure 5).

When SHH reaches its target cell, it binds to the [[PTCH1|Patched-1]] (PTCH1) receptor (Process "3" on Figure 5, the blue molecule). In the absence of ligand, PTCH1 inhibits [[Smoothened]] (SMO), a downstream protein in the pathway (Process "4"). It has been suggested that SMO is regulated by a small molecule, the cellular localization of which is controlled by PTCH.<ref>{{cite journal | vauthors = Taipale J, Cooper MK, Maiti T, Beachy PA | title = Patched acts catalytically to suppress the activity of Smoothened | journal = Nature | volume = 418 | issue = 6900 | pages = 892–897 | date = August 2002 | pmid = 12192414 | doi = 10.1038/nature00989 | s2cid = 4362029 | bibcode = 2002Natur.418..892T }}</ref> [[PTCH1]] has [[Homology (biology)|homology]] to [[Niemann-Pick]] disease, type C1 ([[NPC1]]) that is known to transport [[lipophilic]] molecules across a membrane.<ref>{{cite journal | vauthors = Davies JP, Chen FW, Ioannou YA | title = Transmembrane molecular pump activity of Niemann-Pick C1 protein | journal = Science | volume = 290 | issue = 5500 | pages = 2295–2298 | date = December 2000 | pmid = 11125140 | doi = 10.1126/science.290.5500.2295 | bibcode = 2000Sci...290.2295D }}</ref> PTCH1 has a [[sterol]] sensing domain (SSD), which has been shown to be essential for suppression of SMO activity.<ref>{{cite journal | vauthors = Strutt H, Thomas C, Nakano Y, Stark D, Neave B, Taylor AM, Ingham PW | title = Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation | journal = Current Biology | volume = 11 | issue = 8 | pages = 608–613 | date = April 2001 | pmid = 11369206 | doi = 10.1016/S0960-9822(01)00179-8 | s2cid = 235311937 | doi-access = free | bibcode = 2001CBio...11..608S }}</ref> A current theory suggests that PTCH regulates SMO by removing [[oxysterols]] from SMO. PTCH acts like a sterol pump and removes oxysterols that have been created by [[7-dehydrocholesterol reductase]].<ref>{{cite journal | vauthors = Corcoran RB, Scott MP | title = Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 22 | pages = 8408–8413 | date = May 2006 | pmid = 16707575 | pmc = 1462959 | doi = 10.1073/pnas.0602852103 | doi-access = free | bibcode = 2006PNAS..103.8408C }}</ref> Upon binding of a Hh protein or a mutation in the SSD of PTCH, the pump is turned off allowing oxysterols to accumulate around SMO.  
[[Image:Hedgehog signalling copy.svg|thumb|left|300px|Suggested regulation pathway for Smo via Hedgehog and Ptch1]]
This accumulation of sterols allows SMO to become active or stay on the membrane for a longer period of time. This hypothesis is supported by the existence of a number of small molecule [[agonist]]s and [[antagonist]]s of the pathway that act on SMO. The binding of SHH relieves SMO inhibition, leading to activation of the GLI [[transcription factors]] (Process "5"): the [[Activator (genetics)|activators]] [[Gli1]] and [[Gli2]] and the [[repressor]] [[Gli3]]. The sequence of molecular events that connect SMO to GLIs is poorly understood. Activated GLI accumulates in the nucleus (Process "6") and controls the transcription of hedgehog target genes (Process "7"). PTCH1 has recently been reported to repress transcription of hedgehog target genes through a mechanism independent of [[Smoothened]].<ref name="Rahnama">{{cite journal | vauthors = Rahnama F, Shimokawa T, Lauth M, Finta C, Kogerman P, Teglund S, Toftgård R, Zaphiropoulos PG | display-authors = 6 | title = Inhibition of GLI1 gene activation by Patched1 | journal = The Biochemical Journal | volume = 394 | issue = Pt 1 | pages = 19–26 | date = February 2006 | pmid = 16229683 | pmc = 1385998 | doi = 10.1042/BJ20050941 }}</ref>

In addition to PTCH1, mammals have another hedgehog receptor, PTCH2, whose [[sequence identity]] with PTCH1 is 54%.<ref name="PTCH2">{{cite journal | vauthors = Carpenter D, Stone DM, Brush J, Ryan A, Armanini M, Frantz G, Rosenthal A, de Sauvage FJ | display-authors = 6 | title = Characterization of two patched receptors for the vertebrate hedgehog protein family | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 23 | pages = 13630–13634 | date = November 1998 | pmid = 9811851 | pmc = 24870 | doi = 10.1073/pnas.95.23.13630 | doi-access = free | bibcode = 1998PNAS...9513630C }}</ref> All three mammalian hedgehogs bind both receptors with similar [[chemical affinity|affinity]], so PTCH1 and PTCH2 cannot discriminate between the ligands. They do, however, differ in their expression patterns. PTCH2 is expressed at much higher levels in the [[testis]] and mediates desert hedgehog signaling there.<ref name="PTCH2" /> It appears to have a distinct downstream signaling role from PTCH1. In the absence of [[ligand]] binding PTCH2 has a decreased ability to inhibit the activity of SMO.<ref>{{cite journal | vauthors = Rahnama F, Toftgård R, Zaphiropoulos PG | title = Distinct roles of PTCH2 splice variants in Hedgehog signalling | journal = The Biochemical Journal | volume = 378 | issue = Pt 2 | pages = 325–334 | date = March 2004 | pmid = 14613484 | pmc = 1223965 | doi = 10.1042/BJ20031200 }}</ref> Furthermore, [[overexpression]] of PTCH2 does not replace mutated PTCH1 in [[basal cell carcinoma]].<ref>{{cite journal | vauthors = Zaphiropoulos PG, Undén AB, Rahnama F, Hollingsworth RE, Toftgård R | title = PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas | journal = Cancer Research | volume = 59 | issue = 4 | pages = 787–792 | date = February 1999 | pmid = 10029063 }}</ref>

In invertebrates, just as in ''Drosophila'', the binding of Hedgehog to PTCH leads to [[Internalization (biology)|internalisation]] and sequestration of the ligand.<ref>{{cite journal | vauthors = Incardona JP, Lee JH, Robertson CP, Enga K, Kapur RP, Roelink H | title = Receptor-mediated endocytosis of soluble and membrane-tethered Sonic hedgehog by Patched-1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 22 | pages = 12044–12049 | date = October 2000 | pmid = 11027307 | pmc = 17291 | doi = 10.1073/pnas.220251997 | doi-access = free | bibcode = 2000PNAS...9712044I }}</ref> Consequently, ''in vivo'' the passage of hedgehog over a receptive field that expresses the receptor leads to attenuation of the signal, an effect called ligand-dependent [[Antagonism (chemistry)|antagonism]] (LDA). In contrast to ''Drosophila'', vertebrates possess another level of hedgehog regulation through LDA mediated by Hh-interacting protein 1 (HHIP1). HHIP1 also sequesters hedgehog ligands, but unlike PTCH, it has no effect on the activity of SMO.<ref>{{cite journal | vauthors = Jeong J, McMahon AP | title = Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1 | journal = Development | volume = 132 | issue = 1 | pages = 143–154 | date = January 2005 | pmid = 15576403 | doi = 10.1242/dev.01566 | doi-access = free }}</ref>

===Role===
[[File:Limb bud.svg|thumb|left|300px|'''Figure 6.''' [[Sonic hedgehog (protein)|Sonic hedgehog]] specifies digit identity in mammalian development.]]
Members of the hedgehog family play key roles in a wide variety of developmental processes.<ref name="Ingham2001"/> One of the best studied examples is the action of [[Sonic hedgehog (protein)|Sonic hedgehog]] during development of the vertebrate limb. The classic experiments<ref name="pmid18882505">{{cite journal | vauthors = Saunders JW | title = The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm | journal = The Journal of Experimental Zoology | volume = 108 | issue = 3 | pages = 363–403 | date = August 1948 | pmid = 18882505 | doi = 10.1002/jez.1401080304 | bibcode = 1948JEZ...108..363S }}</ref> of Saunders and Gasseling in 1968<ref>{{cite book | vauthors = Saunders JW, Gasseling MT | chapter = Ectodermal-mesenchymal interactions in the origin of limb symmetry | veditors = Fleischmajer R, Billingham RE | title = Epithelial-Mesenchymal Interactions | publisher = Williams & Wilkins | location = Baltimore | date = 1968 | pages = 78–97 }}</ref> on the development of the chick limb bud formed the basis of the [[morphogen]] concept. They showed that identity of the digits in the chick limb was determined by a [[diffusible]] factor produced by the [[zone of polarizing activity]] (ZPA), a small region of tissue at the [[Posterior (anatomy)|posterior]] margin of the limb. Mammalian development appeared to follow the same pattern. This diffusible factor was later shown to be [[Sonic hedgehog (protein)|Sonic hedgehog]]. However, precisely how SHH determines digit identity remained elusive until recently. The current model, proposed by Harfe ''et al.'',<ref>{{cite journal | vauthors = Harfe BD, Scherz PJ, Nissim S, Tian H, McMahon AP, Tabin CJ | title = Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities | journal = Cell | volume = 118 | issue = 4 | pages = 517–528 | date = August 2004 | pmid = 15315763 | doi = 10.1016/j.cell.2004.07.024 | s2cid = 16280983 | doi-access = free }}</ref> states that both the concentration and the time of exposure to SHH determines which digit the tissue will develop into in the [[mouse]] [[embryo]] (figure 6).

Digits V, IV and part of III arise directly from cells that express SHH during [[embryogenesis]]. In these cells SHH signals in an [[autocrine]] fashion and these digits develop correctly in the absence of DISP, which is required for extracellular diffusion of the ligand. These digits differ in the length of time that SHH continues to be expressed. The most posterior digit V develops from cells that express the ligand for the longest period of time. Digit IV cells express SHH for a shorter time, and digit III cells shorter still. Digit II develops from cells that are exposed to moderate concentrations of extracellular SHH. Finally, Digit I development does not require SHH. It is, in a sense, the default program of limb bud cells.

Hedgehog signaling remains important in the adult. [[Sonic hedgehog (protein)|Sonic hedgehog]] has been shown to promote the proliferation of [[adult stem cell]]s from various tissues, including primitive [[hematopoietic]] cells,<ref>{{cite journal | vauthors = Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE, Karanu FN, Bhatia M | display-authors = 6 | title = Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation | journal = Nature Immunology | volume = 2 | issue = 2 | pages = 172–180 | date = February 2001 | pmid = 11175816 | doi = 10.1038/84282 | s2cid = 27907370 }}</ref> mammary<ref>{{cite journal | vauthors = Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS | display-authors = 6 | title = Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells | journal = Cancer Research | volume = 66 | issue = 12 | pages = 6063–6071 | date = June 2006 | pmid = 16778178 | pmc = 4386278 | doi = 10.1158/0008-5472.CAN-06-0054 }}</ref> and neural<ref>{{cite journal | vauthors = Ahn S, Joyner AL | title = In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog | journal = Nature | volume = 437 | issue = 7060 | pages = 894–897 | date = October 2005 | pmid = 16208373 | doi = 10.1038/nature03994 | s2cid = 4431022 | bibcode = 2005Natur.437..894A }}</ref> stem cells. Activation of the hedgehog pathway is required for transition of the [[hair follicle]] from the resting to the growth phase.<ref>{{cite journal | vauthors = Paladini RD, Saleh J, Qian C, Xu GX, Rubin LL | title = Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway | journal = The Journal of Investigative Dermatology | volume = 125 | issue = 4 | pages = 638–646 | date = October 2005 | pmid = 16185261 | doi = 10.1111/j.0022-202X.2005.23867.x | doi-access = free }}</ref>
This failed due to toxicities found in animal models.<ref>http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=997941&highlight={{full citation needed|date=November 2012}}</ref>

===Human disease===
Disruption of hedgehog signaling during embryonic development, through either deleterious mutation or consumption of [[teratogen]]s by the gestating mother, can lead to severe developmental abnormalities. [[Holoprosencephaly]], the failure of the embryonic [[prosencephalon]] to divide to form cerebral hemispheres, occurs with a frequency of about 1 in 8,000 live births and about 1 in 200 spontaneous abortions in humans and is commonly linked to mutations in genes involved in the hedgehog pathway, including ''SHH'' and ''PTCH''.<ref>{{OMIM|236100|Holoprosencephaly}}</ref> [[Cyclopia]], one of the most severe defects of [[holoprosencephaly]], results if the pathway inhibitor [[cyclopamine]] is consumed by gestating mammals.<ref>{{cite journal | vauthors = Keeler RF | title = Cyclopamine and related steroidal alkaloid teratogens: their occurrence, structural relationship, and biologic effects | journal = Lipids | volume = 13 | issue = 10 | pages = 708–715 | date = October 1978 | pmid = 723484 | doi = 10.1007/BF02533750 | s2cid = 1119899 }}</ref>

Activation of the hedgehog pathway has been implicated in the development of [[cancer]]s in various organs, including [[brain]], [[lung]], [[mammary gland]], [[prostate]] and [[skin]]. [[Basal cell carcinoma]], the most common form of cancerous [[malignancy]], has the closest association with hedgehog signaling. Loss-of-function mutations in [[PTCH1|Patched]] and activating mutations in [[Smoothened]] have been identified in patients with this disease.<ref>{{cite journal | vauthors = Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH, de Sauvage FJ | display-authors = 6 | title = Activating Smoothened mutations in sporadic basal-cell carcinoma | journal = Nature | volume = 391 | issue = 6662 | pages = 90–92 | date = January 1998 | pmid = 9422511 | doi = 10.1038/34201 | s2cid = 205003240 | bibcode = 1998Natur.391...90X }}</ref> Abnormal activation of the pathway probably leads to development of disease through transformation of [[adult stem cell]]s into [[cancer stem cell]]s that give rise to the tumor. Cancer researchers hope that specific inhibitors of hedgehog signaling will provide an efficient therapy for a wide range of malignancies.<ref>{{cite journal | vauthors = Chen JK, Taipale J, Young KE, Maiti T, Beachy PA | title = Small molecule modulation of Smoothened activity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 22 | pages = 14071–14076 | date = October 2002 | pmid = 12391318 | pmc = 137838 | doi = 10.1073/pnas.182542899 | doi-access = free | bibcode = 2002PNAS...9914071C }}</ref>  The connection between the hedgehog signaling  pathway and cancer development is very  complex. Nevertheless, it is clear that the aberrant activation of hedgehog signaling leads to the growth, proliferation, and invasion of tumor cells.<ref name="Skoda_2018">{{cite journal | vauthors = Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L | title = The role of the Hedgehog signaling pathway in cancer: A comprehensive review | journal = Bosnian Journal of Basic Medical Sciences | volume = 18 | issue = 1 | pages = 8–20 | date = February 2018 | pmid = 29274272 | pmc = 5826678 | doi = 10.17305/bjbms.2018.2756 }}</ref> Besides its involvement in the development of [[cancer]]s, hedgehog pathway may also contribute to major respiratory diseases such as pulmonary [[fibrosis]].<ref>{{cite journal | vauthors = Cigna N, Farrokhi Moshai E, Brayer S, Marchal-Somme J, Wémeau-Stervinou L, Fabre A, Mal H, Lesèche G, Dehoux M, Soler P, Crestani B, Mailleux AA | display-authors = 6 | title = The hedgehog system machinery controls transforming growth factor-β-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis | journal = The American Journal of Pathology | volume = 181 | issue = 6 | pages = 2126–2137 | date = December 2012 | pmid = 23031257 | doi = 10.1016/j.ajpath.2012.08.019 | doi-access = free }}</ref> and [[chronic obstructive pulmonary disease]].<ref>{{cite journal | vauthors = Wang C, de Mochel NS, Christenson SA, Cassandras M, Moon R, Brumwell AN, Byrnes LE, Li A, Yokosaki Y, Shan P, Sneddon JB, Jablons D, Lee PJ, Matthay MA, Chapman HA, Peng T | display-authors = 6 | title = Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype | journal = The Journal of Clinical Investigation | volume = 128 | issue = 10 | pages = 4343–4358 | date = October 2018 | pmid = 29999500 | pmc = 6159975 | doi = 10.1172/JCI99435 }}</ref><ref>{{cite journal | vauthors = Ancel J, Belgacemi R, Perotin JM, Diabasana Z, Dury S, Dewolf M, Bonnomet A, Lalun N, Birembaut P, Polette M, Deslée G, Dormoy V | display-authors = 6 | title = Sonic hedgehog signalling as a potential endobronchial biomarker in COPD | journal = Respiratory Research | volume = 21 | issue = 1 | pages = 207 | date = August 2020 | pmid = 32767976 | pmc = 7412648 | doi = 10.1186/s12931-020-01478-x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Belgacemi R, Luczka E, Ancel J, Diabasana Z, Perotin JM, Germain A, Lalun N, Birembaut P, Dubernard X, Mérol JC, Delepine G, Polette M, Deslée G, Dormoy V | display-authors = 6 | title = Airway epithelial cell differentiation relies on deficient Hedgehog signalling in COPD | journal = eBioMedicine | volume = 51 | pages = 102572 | date = January 2020 | pmid = 31877414 | pmc = 6931110 | doi = 10.1016/j.ebiom.2019.11.033 }}</ref>

====Targeting the hedgehog pathway====
{{Main|Hedgehog pathway inhibitor}}
The most common way to target this pathway is modulate SMO. [[Antagonist]] and [[agonist]] of SMO have already shown to affect the pathway regulation downstream. Several hedgehog signaling pathway inhibitors are available for cancer treatment, such as vismodegib and sonidegib. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers. SMO  inhibitors  represent a potential treatment for some types of  cancers.  However,  because of harmful  and  potentially  toxic side-effects  of  SMO  inhibitors,  undetermined  safety  in  children, and the evidence that some patients develop resistance to  SMO inhibitors, new classes of drugs are needed.<ref name="Skoda_2018" />
The most clinically advanced SMO targeting agents are [[cyclopamine]]-competitive. [[Itraconazole]] ([[Sporanox]]) has also been shown to target SMO through a mechanism distinct from [[cyclopamine]] and [[vismodegib]].<ref>{{cite journal | vauthors = Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, Reya T, Liu JO, Epstein EH, Stevens DA, Beachy PA | display-authors = 6 | title = Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth | journal = Cancer Cell | volume = 17 | issue = 4 | pages = 388–399 | date = April 2010 | pmid = 20385363 | pmc = 4039177 | doi = 10.1016/j.ccr.2010.02.027 }}</ref> Itraconazole (ITZ) inhibits SMO in the presence of mutations conferring resistance to [[vismodegib]] and other [[cyclopamine]]-competitive antagonists, like [[IPI-926]] and Novartis' LDE-225.<ref name="Kim, Aftab">{{cite journal | vauthors = Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, Kim J, Chen B, King EM, Borodovsky A, Riggins GJ, Epstein EH, Beachy PA, Rudin CM | display-authors = 6 | title = Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists | journal = Cancer Cell | volume = 23 | issue = 1 | pages = 23–34 | date = January 2013 | pmid = 23291299 | pmc = 3548977 | doi = 10.1016/j.ccr.2012.11.017 }}</ref> PTCH<ref>{{cite journal | vauthors = Nakamura M, Kubo M, Yanai K, Mikami Y, Ikebe M, Nagai S, Yamaguchi K, Tanaka M, Katano M | display-authors = 6 | title = Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation | journal = Anticancer Research | volume = 27 | issue = 6A | pages = 3743–3747 | year = 2007 | pmid = 17970037 }}</ref> and Gli3 (5E1)<ref>{{cite journal | vauthors = Hunt R, Bragina O, Drews M, Kasak L, Timmusk S, Valkna A, Kogerman P, Järvekülg L | display-authors = 6 | title = Generation and characterization of mouse monoclonal antibody 5E1 against human transcription factor GLI3 | journal = Hybridoma | volume = 26 | issue = 4 | pages = 231–240 | date = August 2007 | pmid = 17725385 | doi = 10.1089/hyb.2007.0507 }}</ref> antibodies are also a way to regulate the pathway. A downstream effector and strong transcriptional activator siRNA Gli1 has been used to inhibit cell growth and promote apoptosis.<ref>{{cite journal | vauthors = Stecca B, Mas C, Ruiz i Altaba A | title = Interference with HH-GLI signaling inhibits prostate cancer | journal = Trends in Molecular Medicine | volume = 11 | issue = 5 | pages = 199–203 | date = May 2005 | pmid = 15882606 | doi = 10.1016/j.molmed.2005.03.004 | doi-access = free }}</ref> [[Arsenic trioxide]] ([[Trisenox]]) has also been shown to inhibit hedgehog signaling by interfering with Gli function and transcription.<ref>{{cite journal | vauthors = Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, Peaceman D, Ozdemirli M, Rodriguez O, Macdonald TJ, Albanese C, Toretsky JA, Uren A | display-authors = 6 | title = Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway | journal = The Journal of Clinical Investigation | volume = 121 | issue = 1 | pages = 148–160 | date = January 2011 | pmid = 21183792 | pmc = 3007144 | doi = 10.1172/JCI42874 }}</ref><ref>{{cite journal | vauthors = Kim J, Lee JJ, Kim J, Gardner D, Beachy PA | title = Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 30 | pages = 13432–13437 | date = July 2010 | pmid = 20624968 | pmc = 2922148 | doi = 10.1073/pnas.1006822107 | doi-access = free | bibcode = 2010PNAS..10713432K }}</ref>

Several environmental modifiers of Hedgehog signaling have been identified, which are potential health or developmental hazards. Dietary alkaloids found in tomatoes (tomatodine),<ref name = "Lipinski_2010">{{cite journal | vauthors = Lipinski RJ, Bushman W | title = Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening | journal = Toxicology in Vitro | volume = 24 | issue = 5 | pages = 1404–1409 | date = August 2010 | pmid = 20434536 | pmc = 2891024 | doi = 10.1016/j.tiv.2010.04.011 | publisher = Toxicol In Vitro | bibcode = 2010ToxVi..24.1404L }}</ref> potatoes (solanidine),<ref name = "Lipinski_2010" /> nightshades like peppers and eggplant (solasodine).<ref name = "Lipinski_2010" /> and turmeric (curcumin)<ref>{{cite journal | vauthors = Elamin MH, Shinwari Z, Hendrayani SF, Al-Hindi H, Al-Shail E, Khafaga Y, Al-Kofide A, Aboussekhra A | display-authors = 6 | title = Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells | journal = Molecular Carcinogenesis | volume = 49 | issue = 3 | pages = 302–314 | date = March 2010 | pmid = 20025076 | doi = 10.1002/mc.20604 | s2cid = 31459213 }}</ref> have been shown to antagonize SMO and perturb Hedgehog signaling. In addition, certain environmental toxicants can block Hedgehog signaling. [[Piperonyl butoxide]] (PBO) is a semisynthetic pesticide additive developed in the 1940s, which can be found in thousands of household and agricultural products.<ref>{{cite web | title = Reregistration Eligibility Decision for Piperonyl Butoxide | url = https://archive.epa.gov/pesticides/reregistration/web/pdf/piperonyl_red.pdf |website=USEPA}}</ref> Despite its widespread use, the ability of PBO to inhibit hedgehog signaling and act as a potent developmental teratogen was not recognized until recently.<ref>{{cite journal | vauthors = Wang J, Lu J, Mook RA, Zhang M, Zhao S, Barak LS, Freedman JH, Lyerly HK, Chen W | display-authors = 6 | title = The insecticide synergist piperonyl butoxide inhibits hedgehog signaling: assessing chemical risks | journal = Toxicological Sciences | volume = 128 | issue = 2 | pages = 517–523 | date = August 2012 | pmid = 22552772 | pmc = 3493191 | doi = 10.1093/toxsci/kfs165 }}</ref><ref name="pmid31642701">{{cite journal | vauthors = Everson JL, Sun MR, Fink DM, Heyne GW, Melberg CG, Nelson KF, Doroodchi P, Colopy LJ, Ulschmid CM, Martin AA, McLaughlin MT, Lipinski RJ | display-authors = 6 | title = Developmental Toxicity Assessment of Piperonyl Butoxide Exposure Targeting Sonic Hedgehog Signaling and Forebrain and Face Morphogenesis in the Mouse: An ''in Vitro'' and ''in Vivo'' Study | journal = Environmental Health Perspectives | volume = 127 | issue = 10 | pages = 107006 | date = October 2019 | pmid = 31642701 | pmc = 6867268 | doi = 10.1289/EHP5260 | doi-access = free | bibcode = 2019EnvHP.127j7006E }}</ref>

====Metastasis====
Activation of the Hedgehog pathway leads to an increase in Snail protein expression and a decrease in [[E-cadherin]] and [[tight junction]]s.<ref>{{cite journal | vauthors = Li X, Deng W, Nail CD, Bailey SK, Kraus MH, Ruppert JM, Lobo-Ruppert SM | title = Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation | journal = Oncogene | volume = 25 | issue = 4 | pages = 609–621 | date = January 2006 | pmid = 16158046 | pmc = 1361531 | doi = 10.1038/sj.onc.1209077 }}</ref>

====Tumor regulation====
Activation of the Hedgehog pathway leads to an increase in Angiogenic Factors (angiopoietin-1 and angiopoietin-2),<ref>{{cite journal | vauthors = Lee SW, Moskowitz MA, Sims JR | title = Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts | journal = International Journal of Molecular Medicine | volume = 19 | issue = 3 | pages = 445–451 | date = March 2007 | pmid = 17273793 | doi = 10.3892/ijmm.19.3.445 | doi-access = free }}</ref> Cyclins (cyclin D1 and B1),<ref>{{cite journal | vauthors = Adolphe C, Hetherington R, Ellis T, Wainwright B | title = Patched1 functions as a gatekeeper by promoting cell cycle progression | journal = Cancer Research | volume = 66 | issue = 4 | pages = 2081–2088 | date = February 2006 | pmid = 16489008 | doi = 10.1158/0008-5472.CAN-05-2146 | doi-access = free }}</ref> anti-apoptotic genes and a decrease in apoptotic genes (Fas).<ref>{{cite journal | vauthors = Athar M, Li C, Tang X, Chi S, Zhang X, Kim AL, Tyring SK, Kopelovich L, Hebert J, Epstein EH, Bickers DR, Xie J | display-authors = 6 | title = Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis | journal = Cancer Research | volume = 64 | issue = 20 | pages = 7545–7552 | date = October 2004 | pmid = 15492281 | doi = 10.1158/0008-5472.CAN-04-1393 | doi-access = free }}</ref> Dysfunction or aberrant activation of the Hh signaling pathway is associated with developmental deformities and cancers, including basal cell nevus syndrome (BCNS), basal cell carcinoma (BCC), medulloblastomas (MBs), rhabdomyosarcomas, and meningiomas. Approximately one-third of malignant tumors are linked to the aberrant activation of the Hh pathway. There are three proposed mechanisms of aberrant Hh signaling activation in different cancer types: Type I involves ligand-independent signaling due to mutations in Smo or negative regulators, Type II involves ligand-dependent autocrine/juxtacrine signaling with overexpression of Hh ligand, and Type III involves ligand-dependent paracrine signaling between tumor cells and stromal cells. These dysregulations in the Hh pathway can lead to tumor cell proliferation, survival, and the presence of cancer stem cells, which contribute to tumor initiation and progression.<ref>{{cite journal | vauthors = Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L | title = The role of the Hedgehog signaling pathway in cancer: A comprehensive review | journal = Bosnian Journal of Basic Medical Sciences | volume = 18 | issue = 1 | pages = 8–20 | date = February 2018 | pmid = 29274272 | doi = 10.17305/bjbms.2018.2756 | pmc = 5826678 }}</ref>

====Clinical trials====
* [[Vismodegib]]<ref>{{ClinicalTrialsGov|NCT00636610|A Study of GDC-0449 (Hedgehog Pathway Inhibitor) With Concurrent Chemotherapy and Bevacizumab As First-Line Therapy for Metastatic Colorectal Cancer}}</ref> FDA approved (Jan 2012) for [[basal cell carcinoma]].
* [[Sonidegib]] FDA approved (July 2015) for [[basal cell carcinoma]].
* [[Itraconazole]]<ref>{{ClinicalTrialsGov|NCT01108094|Pilot Biomarker Trial to Evaluate the Efficacy of Itraconazole in Patients w/ Basal Cell Carcinomas}}</ref>

==Evolution==
[[Image:Hedgehog ligand evolution.png|thumb|right|300px|'''Figure 7'''. [[Phylogenetic]] relationship of hedgehog ligands (based on Ingham and McMahon, 2001).]]

[[Lancelet]]s, which are primitive [[chordate]]s, possess only one homologue of ''Drosophila'' ''Hh'' (figure 7). Vertebrates, on the other hand, have several Hedgehog ligands that fall within three subgroups – ''Desert'', ''Indian'' and ''Sonic'', each represented by a single mammalian gene. This is a consequence of the two rounds of whole genome duplication that occurred early in the vertebrate evolutionary history.<ref>{{cite journal | vauthors = Wada H, Makabe K | title = Genome duplications of early vertebrates as a possible chronicle of the evolutionary history of the neural crest | journal = International Journal of Biological Sciences | volume = 2 | issue = 3 | pages = 133–141 | year = 2006 | pmid = 16763673 | pmc = 1474148 | doi = 10.7150/ijbs.2.133 }}</ref> Two such events would have produced four homologous genes, one of which must have been lost. Desert Hedgehogs are the most closely related to ''Drosophila'' ''Hh''. Additional gene duplications occurred within some species<ref name="Ingham2001" /> such as the [[zebrafish]] ''Danio rerio'', which has an additional ''tiggywinkle hedgehog'' gene in the ''sonic'' group. Various vertebrate lineages have adapted hedgehogs to unique developmental processes. For example, a homologue of the ''X.laevis'' ''banded hedgehog'' is involved in regeneration of the [[salamander]] limb.<ref>{{cite journal | vauthors = Stark DR, Gates PB, Brockes JP, Ferretti P | title = Hedgehog family member is expressed throughout regenerating and developing limbs | journal = Developmental Dynamics | volume = 212 | issue = 3 | pages = 352–363 | date = July 1998 | pmid = 9671939 | doi = 10.1002/(SICI)1097-0177(199807)212:3<352::AID-AJA3>3.0.CO;2-G | doi-access = free }}</ref>

''shh'' has undergone accelerated evolution in the primate lineage leading to humans.<ref>{{cite journal | vauthors = Dorus S, Anderson JR, Vallender EJ, Gilbert SL, Zhang L, Chemnick LG, Ryder OA, Li W, Lahn BT | display-authors = 6 | title = Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates | journal = Human Molecular Genetics | volume = 15 | issue = 13 | pages = 2031–2037 | date = July 2006 | pmid = 16687440 | doi = 10.1093/hmg/ddl123 | doi-access = free }}</ref> Dorus ''et al.'' hypothesise that this allowed for more complex regulation of the protein and may have played a role in the increase in volume and complexity of the human brain.

The frizzled family of [[Wnt signaling pathway|WNT]] receptors have some sequence similarity to [[Smoothened]].<ref name="Graul2001">{{cite journal | vauthors = Graul RC, Sadée W | title = Evolutionary relationships among G protein-coupled receptors using a clustered database approach | journal = AAPS PharmSci | volume = 3 | issue = 2 | pages = 25–42 | year = 2001 | pmid = 11741263 | pmc = 2779559 | doi = 10.1208/ps030212 }}</ref> Smoothened seems to be a functionally divergent member of the [[G protein-coupled receptor]] (GPCR) superfamily. Other similarities between the WNT and Hh signaling pathways have been reviewed.<ref name="Nusse2003">{{cite journal | vauthors = Nusse R | title = Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface | journal = Development | volume = 130 | issue = 22 | pages = 5297–5305 | date = November 2003 | pmid = 14530294 | doi = 10.1242/dev.00821 | doi-access = free }}</ref> Nusse observed that, "a signalling system based on lipid-modified proteins and specific membrane translocators is ancient, and may have been the founder of the Wnt and Hh signaling systems".

It has been suggested that invertebrate and vertebrate signalling downstream from Smoothened has diverged significantly.<ref name="Varjosalo2006">{{cite journal | vauthors = Varjosalo M, Li SP, Taipale J | title = Divergence of hedgehog signal transduction mechanism between Drosophila and mammals | journal = Developmental Cell | volume = 10 | issue = 2 | pages = 177–186 | date = February 2006 | pmid = 16459297 | doi = 10.1016/j.devcel.2005.12.014 | doi-access = free }}</ref> The role of Suppressor of Fused (SUFU) has been enhanced in vertebrates compared to ''Drosophila'' where its role is relatively minor. Costal-2 is particularly important in ''Drosophila''. The protein kinase Fused is a regulator of SUFU in ''Drosophila'', but may not play a role in the Hh pathway of vertebrates.<ref name="Chen2006">{{cite journal | vauthors = Chen MH, Gao N, Kawakami T, Chuang PT | title = Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development | journal = Molecular and Cellular Biology | volume = 25 | issue = 16 | pages = 7042–7053 | date = August 2005 | pmid = 16055716 | pmc = 1190231 | doi = 10.1128/MCB.25.16.7042-7053.2005 }}</ref> In vertebrates, Hh signalling has been heavily implicated in the development of [[cilia]].<ref name="Huangfu2006">{{cite journal | vauthors = Huangfu D, Anderson KV | title = Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates | journal = Development | volume = 133 | issue = 1 | pages = 3–14 | date = January 2006 | pmid = 16339192 | doi = 10.1242/dev.02169 | doi-access = free }}</ref>

There is striking domain level evolution present in the Hedgehog family of proteins, the N-terminal domain (Hedge) and the C-terminal domain (Hog), that were later spliced together into a single transcriptional unit.<ref name="Matus2008">{{cite journal | vauthors = Matus DQ, Magie CR, Pang K, Martindale MQ, Thomsen GH | title = The Hedgehog gene family of the cnidarian, Nematostella vectensis, and implications for understanding metazoan Hedgehog pathway evolution | journal = Developmental Biology | volume = 313 | issue = 2 | pages = 501–518 | date = January 2008 | pmid = 18068698 | pmc = 2288667 | doi = 10.1016/j.ydbio.2007.09.032 }}</ref><ref name="Doicub">{{cite journal | vauthors = Adamska M, Matus DQ, Adamski M, Green K, Rokhsar DS, Martindale MQ, Degnan BM | title = The evolutionary origin of hedgehog proteins | journal = Current Biology | volume = 17 | issue = 19 | pages = R836–R837 | date = October 2007 | pmid = 17925209 | doi = 10.1016/j.cub.2007.08.010 | s2cid = 15158554 | doi-access = free | bibcode = 2007CBio...17.R836A }}</ref> The Hog domain contains a sequence called Hint (Hedgehog INTein), which is similar in sequence and function to bacterial and fungal [[intein]]s.<ref name="Doirspb">{{cite journal | vauthors = Snell EA, Brooke NM, Taylor WR, Casane D, Philippe H, Holland PW | title = An unusual choanoflagellate protein released by Hedgehog autocatalytic processing | journal = Proceedings. Biological Sciences | volume = 273 | issue = 1585 | pages = 401–407 | date = February 2006 | pmid = 16615205 | pmc = 1560198 | doi = 10.1098/rspb.2005.3263 }}</ref> The Hog domain is present in many eukaryotic branches, i.e. red algae, mosses, dinoflagellates, jakobids, and other single cell eurkaryotes.<ref name="Burglin2008">{{cite journal | vauthors = Bürglin TR | title = Evolution of hedgehog and hedgehog-related genes, their origin from Hog proteins in ancestral eukaryotes and discovery of a novel Hint motif | journal = BMC Genomics | volume = 9 | issue = 127 | pages = 127 | date = March 2008 | pmid = 18334026 | pmc = 2362128 | doi = 10.1186/1471-2164-9-127 | doi-access = free }}</ref> [[Choanoflagellate]]s contain a gene named hoglet that also encodes the hedgehog C-terminal domain Hog domain. However, Choanoflagellates and lower eukaryotes do not contain any regions similar to the hedge domain, suggesting that hog evolved first.<ref name="Doirspb" /><ref name="Burglin2008" /> [[Sponge|Poriferans]] have both hedge-like proteins (termed hedgling) and hog-like proteins, but they exist as two completely separate transcriptional units.<ref name="Matus2008" /><ref name="Doicub" /> [[Cnidaria]]ns contain the hedgling and hog genes, but also have a complete hedgehog gene, indicating that hedge and hog were spliced into hedgehog after the last common ancestor of poriferans and cnidarians.<ref name="Doicub" />

Bilaterians do not contain hedgling genes, suggesting that these were lost by deletion before this branch split from the other metazoans.<ref name="Doinrg" /> However, Hog domain-containing genes without a Hedge domain are present in several bilaterian lineages. They are found in [[Lophotrochozoa]] and [[Nematode|Nematoda]].<ref name="Burglin2008b">{{cite journal | vauthors = Bürglin TR | title = The Hedgehog protein family | journal = Genome Biology | volume = 9 | issue = 11 | pages = 241 | year = 2008 | pmid = 19040769 | pmc = 2614485 | doi = 10.1186/gb-2008-9-11-241 | doi-access = free }}</ref> Hedgehog-like genes, 2 Patched homologs and Patched-related genes exist in the worm ''[[Caenorhabditis elegans|C. elegans]]''.<ref name="Zugasti2005">{{cite journal | vauthors = Zugasti O, Rajan J, Kuwabara PE | title = The function and expansion of the Patched- and Hedgehog-related homologs in C. elegans | journal = Genome Research | volume = 15 | issue = 10 | pages = 1402–1410 | date = October 2005 | pmid = 16204193 | pmc = 1240083 | doi = 10.1101/gr.3935405 }}</ref><ref name="Burglin2006">{{cite journal | vauthors = Bürglin TR, Kuwabara PE | title = Homologs of the Hh signalling network in C. elegans | journal = WormBook | pages = 1–14 | date = January 2006 | pmid = 18050469 | pmc = 4781598 | doi = 10.1895/wormbook.1.76.1 }}</ref> These genes have been shown to code for proteins that have roles in ''C. elegans'' development.<ref name="Zugasti2005" /><ref name="Burglin2006" /> Whilst [[Enoplea]] nematodes have retained a bona-fide Hedgehog, [[Chromadorea]]ns have lost the archetypal Hedgehog and have instead evolved an expanded repertoire of 61 divergent semi-orthologous genes with novel N-terminal domains associated with Hog.<ref name="Burglin2008" /><ref name="Burglin2008b" /> These N-terminal domains associated with Hog in ''C. elegans'' were subsequently classified, initially Warthog (WRT) and Groundhog (GRD), followed by Ground-like (GRL) and Quahog (QUA).<ref name="Zugasti2005"/><ref name="Burglin2006"/> ''C. elegans'', along with other nematode species, have lost the GPCR Smoothened.<ref name="Zugasti2005" /><ref name="Burglin2006" />

The ultimate origin of the Hedgehog signaling pathway is hypothesized to be a bacterial regulatory pathway of [[hopanoids]] that are common [[lipid]] components in bacteria and are structural analogs of [[steroid]]s.<ref>{{cite journal | vauthors = Hausmann G, von Mering C, Basler K | title = The hedgehog signaling pathway: where did it come from? | journal = PLOS Biology | volume = 7 | issue = 6 | pages = e1000146 | date = June 2009 | pmid = 19564910 | pmc = 2698682 | doi = 10.1371/journal.pbio.1000146 | doi-access = free }}</ref>

== See also ==
* [[Sonic hedgehog (protein)|Sonic hedgehog]], best studied ligand of the vertebrate pathway
* [[Smoothened]], the conserved [[GPCR]] component of the pathway
* [[Netpath]] – A curated resource of signal transduction pathways in humans
* Inhibitors of Hh signaling
** [[Cyclopamine]], a naturally occurring small molecule
** [[Sonidegib]]
** [[Vismodegib]], approved for [[basal cell carcinoma]].

== References ==
{{Reflist|2}}

== External links ==
{{Commons category}}
* {{cite web | vauthors = Ramirez-Weber FA | location = San Francisco, CA | publisher =  San Francisco State University | url = http://hedgehog.sfsu.edu/ | title = Hedgehog Pathway Database | archive-url = https://web.archive.org/web/20060716083827/http://hedgehog.sfsu.edu/ | archive-date = 16 July 2006 }}
* {{cite web | url = http://www.novusbio.com/hedgehogpathway.html | title = Hedgehog Signaling Pathway Diagram | work = Novus Biologicals }}

{{Cell signaling}}
{{Hedgehog signaling pathway}}
{{genarch}}
{{Authority control}}

[[Category:Hedgehog signaling pathway| ]]
[[Category:Cell signaling]]
[[Category:Evolutionary developmental biology]]