Hedgehog signaling pathway

622:(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. 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. It has been suggested that phosphorylation of Smoothened plays a role in Hh-dependent regulation of Smoothened levels. 651: 1248:

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.

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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. The most clinically advanced SMO targeting agents are

904:. 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 1329:, 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. Two such events would have produced four homologous genes, one of which must have been lost. Desert Hedgehogs are the most closely related to 1247:

Activation of the Hedgehog pathway leads to an increase in Angiogenic Factors (angiopoietin-1 and angiopoietin-2), Cyclins (cyclin D1 and B1), anti-apoptotic genes and a decrease in apoptotic genes (Fas). Dysfunction or aberrant activation of the Hh signaling pathway is associated with developmental

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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.

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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. The Hog domain contains a sequence called Hint (Hedgehog INTein), which is similar

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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. The connection between the hedgehog signaling pathway and cancer development is very complex. Nevertheless, it is clear that the

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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

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Several environmental modifiers of Hedgehog signaling have been identified, which are potential health or developmental hazards. Dietary alkaloids found in tomatoes (tomatodine), potatoes (solanidine), nightshades like peppers and eggplant (solasodine). and turmeric (curcumin) have been shown to

1223:(PBO) is a semisynthetic pesticide additive developed in the 1940s, which can be found in thousands of household and agricultural products. Despite its widespread use, the ability of PBO to inhibit hedgehog signaling and act as a potent developmental teratogen was not recognized until recently. 1027:

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.

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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

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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

1387:(GPCR) superfamily. Other similarities between the WNT and Hh signaling pathways have been reviewed. 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". 396: 1431:

Bilaterians do not contain hedgling genes, suggesting that these were lost by deletion before this branch split from the other metazoans. However, Hog domain-containing genes without a Hedge domain are present in several bilaterian lineages. They are found in

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as well as features on adult appendages such as legs and antennae. 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

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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

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isolated mutations in genes that control development of the segmented anterior-posterior body axis of the fly; their "saturation mutagenesis" technique resulted in the discovery of a group of genes involved in the development of

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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.

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and Novartis' LDE-225. PTCH and Gli3 (5E1) 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.

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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. These N-terminal domains associated with Hog in

958:, 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. 752:

seems unlikely, this suggests a common origin of segmentation between the two phyla. Whilst Hh does not induce the formation of segments, it seems to act to stabilize the segmented fields once they have appeared.

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Aspiras AC, Prasad R, Fong DW, Carlini DB, Angelini DR (May 2012). "Parallel reduction in expression of the eye development gene hedgehog in separately derived cave populations of the amphipod Gammarus minus".

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Elamin MH, Shinwari Z, Hendrayani SF, Al-Hindi H, Al-Shail E, Khafaga Y, et al. (March 2010). "Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells".

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It has been suggested that invertebrate and vertebrate signalling downstream from Smoothened has diverged significantly. The role of Suppressor of Fused (SUFU) has been enhanced in vertebrates compared to

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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.

272:. 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 2743:

Zaphiropoulos PG, Undén AB, Rahnama F, Hollingsworth RE, Toftgård R (February 1999). "PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas".

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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

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Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, et al. (February 2001). "Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation".

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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.

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Hunt R, Bragina O, Drews M, Kasak L, Timmusk S, Valkna A, et al. (August 2007). "Generation and characterization of mouse monoclonal antibody 5E1 against human transcription factor GLI3".

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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

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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).

831:(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. 3680:

Nakamura M, Kubo M, Yanai K, Mikami Y, Ikebe M, Nagai S, et al. (2007). "Anti-patched-1 antibodies suppress hedgehog signaling pathway and pancreatic cancer proliferation".

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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

1955:

Chen W, Ren XR, Nelson CD, Barak LS, Chen JK, Beachy PA, et al. (December 2004). "Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2".

637:. 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 2047:

Apionishev S, Katanayeva NM, Marks SA, Kalderon D, Tomlinson A (January 2005). "Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction".

3394:"The hedgehog system machinery controls transforming growth factor-β-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis" 984:

during development of the vertebrate limb. The classic experiments of Saunders and Gasseling in 1968 on the development of the chick limb bud formed the basis of the

209: 919:, 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 457:) 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 1608: 1372:

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.

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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

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for "A Study of GDC-0449 (Hedgehog Pathway Inhibitor) With Concurrent Chemotherapy and Bevacizumab As First-Line Therapy for Metastatic Colorectal Cancer" at

5595: 4061:"Developmental Toxicity Assessment of Piperonyl Butoxide Exposure Targeting Sonic Hedgehog Signaling and Forebrain and Face Morphogenesis in the Mouse: An 2831:"Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1" 633:

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

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have been identified in patients with this disease. Abnormal activation of the pathway probably leads to development of disease through transformation of

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sensing domain (SSD), which has been shown to be essential for suppression of SMO activity. A current theory suggests that PTCH regulates SMO by removing

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aberrant activation of hedgehog signaling leads to the growth, proliferation, and invasion of tumor cells. Besides its involvement in the development of

784:(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 3633:"Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists" 473:

embryos. The function of the hedgehog segment polarity gene has been studied for influence on the normally polarized distribution of larval cuticular

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Keeler RF (October 1978). "Cyclopamine and related steroidal alkaloid teratogens: their occurrence, structural relationship, and biologic effects".

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Hedgehog has roles in larval body segment development and in formation of adult appendages. During the formation of body segments in the developing

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gene has an upstream transcription regulatory region that binds the Ci transcription factor in a Hh-dependent fashion resulting in an increase in

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Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. (January 1998). "Activating Smoothened mutations in sporadic basal-cell carcinoma".

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Saunders JW, Gasseling MT (1968). "Ectodermal-mesenchymal interactions in the origin of limb symmetry". In Fleischmajer R, Billingham RE (eds.).

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the passage of hedgehog over a receptive field that expresses the receptor leads to attenuation of the signal, an effect called ligand-dependent

1415:. The Hog domain is present in many eukaryotic branches, i.e. red algae, mosses, dinoflagellates, jakobids, and other single cell eurkaryotes. 343:, of which Sonic is the best studied. The pathway is equally important during vertebrate embryonic development and is therefore of interest in 4892:"Evolution of hedgehog and hedgehog-related genes, their origin from Hog proteins in ancestral eukaryotes and discovery of a novel Hint motif" 980:

Members of the hedgehog family play key roles in a wide variety of developmental processes. One of the best studied examples is the action of

5203: 4251:"Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis" 1403:, but may not play a role in the Hh pathway of vertebrates. In vertebrates, Hh signalling has been heavily implicated in the development of 4732:"The Hedgehog gene family of the cnidarian, Nematostella vectensis, and implications for understanding metazoan Hedgehog pathway evolution" 6258: 3834:"Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector" 3160: 1424:

have both hedge-like proteins (termed hedgling) and hog-like proteins, but they exist as two completely separate transcriptional units.

863:. 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. 4639:"Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development" 808:

end of the N-terminal domain, which is involved in trafficking, secretion and receptor interaction of the ligand. SHH can signal in an

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and mediates desert hedgehog signaling there. It appears to have a distinct downstream signaling role from PTCH1. In the absence of

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Wingless protein acts as an extracellular signal and patterns the adjacent rows of cells by activating its cell surface receptor

38: 2870:

Saunders JW (August 1948). "The proximo-distal sequence of origin of the parts of the chick wing and the role of the ectoderm".

1008:, states that both the concentration and the time of exposure to SHH determines which digit the tissue will develop into in the 6229: 424: 2381:

Taipale J, Cooper MK, Maiti T, Beachy PA (August 2002). "Patched acts catalytically to suppress the activity of Smoothened".

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group. Various vertebrate lineages have adapted hedgehogs to unique developmental processes. For example, a homologue of the

1148: 1004:. However, precisely how SHH determines digit identity remained elusive until recently. The current model, proposed by Harfe 432: 157: 1000:

margin of the limb. Mammalian development appeared to follow the same pattern. This diffusible factor was later shown to be

707:. Wingless acts on engrailed-expressing cells to stabilize the stripes of engrailed expression. Wingless is a member of the 229: 1463:

were subsequently classified, initially Warthog (WRT) and Groundhog (GRD), followed by Ground-like (GRL) and Quahog (QUA).

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and Saigo Kaoru. Some hedgehog mutants result in abnormally-shaped embryos that are unusually short and stubby compared to

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antagonize SMO and perturb Hedgehog signaling. In addition, certain environmental toxicants can block Hedgehog signaling.

6248: 6194: 5581: 5450: 3171: 6039: 5767: 5418: 3069:

Ahn S, Joyner AL (October 2005). "In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog".

1616: 428: 344: 2008:"Posttranscriptional regulation of smoothened is part of a self-correcting mechanism in the Hedgehog signaling system" 383:. Drugs that specifically target Hedgehog signaling to fight this disease are being actively developed by a number of 5739: 5196: 2477:"Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation" 1054:

Disruption of hedgehog signaling during embryonic development, through either deleterious mutation or consumption of

2432:

Davies JP, Chen FW, Ioannou YA (December 2000). "Transmembrane molecular pump activity of Niemann-Pick C1 protein".

5996: 5782: 5777: 3785:"Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway" 4377:"Genome duplications of early vertebrates as a possible chronicle of the evolutionary history of the neural crest" 3392:

Cigna N, Farrokhi Moshai E, Brayer S, Marchal-Somme J, Wémeau-Stervinou L, Fabre A, et al. (December 2012).

2133:"Hedgehog signaling regulates transcription through cubitus interruptus, a sequence-specific DNA binding protein" 1676:

Nüsslein-Volhard C, Wieschaus E (October 1980). "Mutations affecting segment number and polarity in Drosophila".

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Ingham PW, Nakano Y, Seger C (June 2011). "Mechanisms and functions of Hedgehog signalling across the metazoa".

4688:"Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates" 860: 6173: 3989: 1470:

The ultimate origin of the Hedgehog signaling pathway is hypothesized to be a bacterial regulatory pathway of

415: 217: 6024: 4362:

for "Pilot Biomarker Trial to Evaluate the Efficacy of Itraconazole in Patients w/ Basal Cell Carcinomas" at

1317:(figure 7). Vertebrates, on the other hand, have several Hedgehog ligands that fall within three subgroups – 882:

of the pathway that act on SMO. The binding of SHH relieves SMO inhibition, leading to activation of the GLI

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transcription (interaction 2 in Figure 3) in a stripe of cells adjacent to the stripe of Hh-producing cells.

580: 1792:"Requirements for hedgehog, a segmental polarity gene, in patterning larval and adult cuticle of Drosophila" 5445: 5189: 1042:

cells, mammary and neural stem cells. Activation of the hedgehog pathway is required for transition of the

4557:"Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface" 4120:"Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation" 3898:"Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening" 5991: 993: 516:. When Hh is bound to Patched (PTCH), Ci protein is able to act as a transcription factor in the nucleus. 1778: 1215:) has also been shown to inhibit hedgehog signaling by interfering with Gli function and transcription. 827:(PTCH1) receptor (Process "3" on Figure 5, the blue molecule). In the absence of ligand, PTCH1 inhibits 279:

The Hedgehog signaling pathway is one of the key regulators of animal development and is present in all

6183: 5881: 5264: 5247: 5230: 5158: 4169:"Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts" 1384: 1160: 630: 213: 3161:

http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=997941&highlight=

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Dray N, Tessmar-Raible K, Le Gouar M, Vibert L, Christodoulou F, Schipany K, et al. (July 2010).

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Activation of the Hedgehog pathway leads to an increase in Snail protein expression and a decrease in

5876: 5634: 5629: 5460: 5455: 5269: 3433:

Wang C, de Mochel NS, Christenson SA, Cassandras M, Moon R, Brumwell AN, et al. (October 2018).

3022:"Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells" 1727:

Arthur W (February 2002). "The emerging conceptual framework of evolutionary developmental biology".

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hedgehog signaling require the participation of Dispatched (DISP) protein (Process "2" on Figure 5).

634: 336: 332: 170: 4012:"The insecticide synergist piperonyl butoxide inhibits hedgehog signaling: assessing chemical risks" 3584:"Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth" 2526:"Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells" 1916: 5624: 5552: 5242: 1844:"A genetic screen in Drosophila for identifying novel components of the hedgehog signaling pathway" 1491: 1031: 1001: 981: 973: 440: 4508:"Evolutionary relationships among G protein-coupled receptors using a clustered database approach" 2092:"Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused" 1558:"Hedgehog Pathway Inhibitors: A New Therapeutic Class for the Treatment of Acute Myeloid Leukemia" 6253: 6117: 6054: 6029: 5912: 5832: 5644: 5380: 5352: 5279: 5259: 4467:"Sonic Hedgehog, a key development gene, experienced intensified molecular evolution in primates" 2930:"Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities" 724: 325: 5573: 3533:

Belgacemi R, Luczka E, Ancel J, Diabasana Z, Perotin JM, Germain A, et al. (January 2020).

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fail to develop correctly. Recent studies point to the role of Hedgehog signaling in regulating

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Dorus S, Anderson JR, Vallender EJ, Gilbert SL, Zhang L, Chemnick LG, et al. (July 2006).

1911: 1894:

Lum L, Beachy PA (June 2004). "The Hedgehog response network: sensors, switches, and routers".

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Adamska M, Matus DQ, Adamski M, Green K, Rokhsar DS, Martindale MQ, Degnan BM (October 2007).

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Rahnama F, Shimokawa T, Lauth M, Finta C, Kogerman P, Teglund S, et al. (February 2006).

6213: 6107: 6034: 5933: 5871: 5866: 5797: 5732: 5518: 5480: 5360: 5306: 5284: 5237: 1376: 883: 708: 685: 658: 407: 313: 287: 3482:

Ancel J, Belgacemi R, Perotin JM, Diabasana Z, Dury S, Dewolf M, et al. (August 2020).

2772:"Receptor-mediated endocytosis of soluble and membrane-tethered Sonic hedgehog by Patched-1" 1046:

from the resting to the growth phase. This failed due to toxicities found in animal models.

551:-dependent cleavage, which generates a 75 kDa fragment (CiR). CiR builds up in the cell and 6122: 5965: 5960: 5842: 5837: 5824: 5667: 5489: 5485: 5437: 3845: 3294: 3239: 3078: 2879: 2783: 2648: 2635:

Carpenter D, Stone DM, Brush J, Ryan A, Armanini M, Frantz G, et al. (November 1998).

2537: 2441: 2390: 2296: 2144: 1964: 1903: 1736: 1685: 1531: 1271: 1261: 1115: 932: 887: 678: 670: 529: 269: 196: 4059:

Everson JL, Sun MR, Fink DM, Heyne GW, Melberg CG, Nelson KF, et al. (October 2019).

3122:"Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway" 78: 8: 6218: 5604: 5547: 5530: 5216: 3783:

Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, et al. (January 2011).

997: 532: 5004:"The function and expansion of the Patched- and Hedgehog-related homologs in C. elegans" 4118:

Li X, Deng W, Nail CD, Bailey SK, Kraus MH, Ruppert JM, Lobo-Ruppert SM (January 2006).

3849: 3535:"Airway epithelial cell differentiation relies on deficient Hedgehog signalling in COPD" 3298: 3243: 3082: 2883: 2787: 2652: 2541: 2445: 2394: 2300: 2148: 1968: 1907: 1740: 1689: 1194:. Itraconazole (ITZ) inhibits SMO in the presence of mutations conferring resistance to 859:

from SMO. PTCH acts like a sterol pump and removes oxysterols that have been created by

727:

to coordinate wing formation. Hedgehog is expressed in the posterior part of developing

5907: 5289: 5181: 5131: 5104: 5080: 5059: 5028: 5003: 4972: 4945: 4918: 4891: 4862: 4837: 4815: 4756: 4731: 4663: 4638: 4532: 4507: 4401: 4376: 4363: 4345: 4316: 4291: 4144: 4119: 4095: 4060: 4036: 4011: 3971: 3922: 3897: 3868: 3833: 3809: 3784: 3657: 3632: 3608: 3583: 3559: 3534: 3510: 3483: 3459: 3434: 3369: 3344: 3263: 3212: 3102: 3046: 3021: 3002: 2959: 2720: 2695: 2609: 2584: 2560: 2525: 2506: 2414: 2317: 2284: 2262: 2072: 1988: 1937: 1868: 1843: 1816: 1791: 1760: 1709: 1658: 1584: 1557: 1220: 1143:, hedgehog pathway may also contribute to major respiratory diseases such as pulmonary 988:

concept. They showed that identity of the digits in the chick limb was determined by a

836: 749: 466: 3317: 3282: 2637:"Characterization of two patched receptors for the vertebrate hedgehog protein family" 2493: 2476: 2024: 2007: 1440:. Hedgehog-like genes, 2 Patched homologs and Patched-related genes exist in the worm 6168: 5948: 5943: 5852: 5397: 5136: 5085: 5033: 4977: 4923: 4867: 4807: 4761: 4709: 4668: 4654: 4619: 4598:"Divergence of hedgehog signal transduction mechanism between Drosophila and mammals" 4578: 4537: 4488: 4447: 4406: 4321: 4272: 4231: 4190: 4149: 4100: 4041: 3963: 3927: 3873: 3814: 3765: 3724: 3689: 3662: 3613: 3564: 3515: 3464: 3435:"Expansion of hedgehog disrupts mesenchymal identity and induces emphysema phenotype" 3415: 3374: 3322: 3267: 3255: 3204: 3143: 3138: 3121: 3094: 3051: 2994: 2951: 2895: 2852: 2811: 2806: 2771: 2752: 2725: 2676: 2671: 2636: 2614: 2565: 2510: 2498: 2457: 2406: 2363: 2322: 2254: 2250: 2218: 2172: 2167: 2132: 2113: 2064: 2029: 1980: 1929: 1873: 1821: 1752: 1701: 1650: 1589: 1122:, has the closest association with hedgehog signaling. Loss-of-function mutations in 1080: 1059: 916: 912: 376: 261: 204: 162: 6152: 4819: 3975: 3006: 2963: 2266: 1992: 1941: 1662: 1368:

has undergone accelerated evolution in the primate lineage leading to humans. Dorus

126: 6178: 6147: 6142: 6097: 5725: 5523: 5494: 5423: 5319: 5252: 5126: 5116: 5075: 5067: 5023: 5015: 4967: 4957: 4913: 4903: 4857: 4849: 4838:"An unusual choanoflagellate protein released by Hedgehog autocatalytic processing" 4797: 4751: 4743: 4699: 4658: 4650: 4609: 4568: 4527: 4519: 4478: 4437: 4396: 4388: 4311: 4303: 4262: 4221: 4180: 4139: 4131: 4090: 4080: 4031: 4023: 3955: 3917: 3909: 3863: 3853: 3804: 3796: 3755: 3716: 3652: 3644: 3603: 3595: 3554: 3546: 3505: 3495: 3454: 3446: 3405: 3364: 3356: 3312: 3302: 3247: 3216: 3196: 3133: 3106: 3086: 3041: 3033: 2986: 2941: 2887: 2842: 2801: 2791: 2715: 2707: 2666: 2656: 2604: 2596: 2555: 2545: 2488: 2475:

Strutt H, Thomas C, Nakano Y, Stark D, Neave B, Taylor AM, Ingham PW (April 2001).

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binding PTCH2 has a decreased ability to inhibit the activity of SMO. Furthermore,

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Snell EA, Brooke NM, Taylor WR, Casane D, Philippe H, Holland PW (February 2006).

4426:"Hedgehog family member is expressed throughout regenerating and developing limbs" 4358: 4340: 4267: 4250: 4226: 4209: 3037: 2453: 1807: 1574: 915:

with PTCH1 is 54%. All three mammalian hedgehogs bind both receptors with similar

539:-like protein Costal-2 (Cos2) and is localized in the cytoplasm bound to cellular 6188: 6092: 5902: 5402: 5121: 4614: 4597: 3760: 3743: 3410: 3393: 3020:

Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, et al. (June 2006).

1131: 1035: 626: 588: 572: 474: 436: 372: 246: 138: 4747: 3550: 2770:

Incardona JP, Lee JH, Robertson CP, Enga K, Kapur RP, Roelink H (October 2000).

1859: 88: 5717: 5535: 5342: 5212: 5170: 3838: