SHH_MOUSE
ID SHH_MOUSE Reviewed; 437 AA.
AC Q62226;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 2.
DT 03-AUG-2022, entry version 212.
DE RecName: Full=Sonic hedgehog protein {ECO:0000305};
DE Short=SHH;
DE EC=3.1.-.- {ECO:0000269|PubMed:8824192};
DE AltName: Full=HHG-1;
DE AltName: Full=Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains {ECO:0000303|PubMed:24522195};
DE Short=ShhNC {ECO:0000303|PubMed:24522195};
DE Contains:
DE RecName: Full=Sonic hedgehog protein N-product;
DE Short=ShhN;
DE AltName: Full=Shh N-terminal processed signaling domains {ECO:0000303|PubMed:24522195};
DE Short=ShhNp {ECO:0000303|PubMed:24522195};
DE AltName: Full=Sonic hedgehog protein 19 kDa product;
DE Flags: Precursor;
GN Name=Shh {ECO:0000312|MGI:MGI:98297}; Synonyms=Hhg1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryo;
RX PubMed=7916661; DOI=10.1016/0092-8674(93)90627-3;
RA Echelard Y., Epstein D.J., St Jacques B., Shen L., Mohler J., McMahon J.A.,
RA McMahon A.P.;
RT "Sonic hedgehog, a member of a family of putative signaling molecules, is
RT implicated in the regulation of CNS polarity.";
RL Cell 75:1417-1430(1993).
RN [2]
RP SEQUENCE REVISION TO 122.
RA McMahon A.P.;
RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEOLYTIC PROCESSING, AND AUTOCATALYTIC
RP CLEAVAGE.
RX PubMed=7720571; DOI=10.1242/dev.120.11.3339;
RA Chang D.T., Lopez A., von Kessler D.P., Chiang C., Simandl B.K., Zhao R.,
RA Seldin M.F., Fallon J.F., Beachy P.A.;
RT "Products, genetic linkage and limb patterning activity of a murine
RT hedgehog gene.";
RL Development 120:3339-3353(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Limb;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PROTEOLYTIC PROCESSING, GLYCOSYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=7891723; DOI=10.1128/mcb.15.4.2294;
RA Bumcrot D.A., Takada R., McMahon A.P.;
RT "Proteolytic processing yields two secreted forms of sonic hedgehog.";
RL Mol. Cell. Biol. 15:2294-2303(1995).
RN [7]
RP FUNCTION, PROTEOLYTIC PROCESSING, AND AUTOCATALYTIC CLEAVAGE.
RX PubMed=7736596; DOI=10.1016/0092-8674(95)90397-6;
RA Roelink H., Porter J.A., Chiang C., Tanabe Y., Chang D.T., Beachy P.A.,
RA Jessell T.M.;
RT "Floor plate and motor neuron induction by different concentrations of the
RT amino-terminal cleavage product of sonic hedgehog autoproteolysis.";
RL Cell 81:445-455(1995).
RN [8]
RP CHOLESTERYLATION AT GLY-198, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=8824192; DOI=10.1126/science.274.5285.255;
RA Porter J.A., Young K.E., Beachy P.A.;
RT "Cholesterol modification of hedgehog signaling proteins in animal
RT development.";
RL Science 274:255-259(1996).
RN [9]
RP PALMITOYLATION AT CYS-25, AND MUTAGENESIS OF CYS-25.
RX PubMed=11486055; DOI=10.1126/science.1064437;
RA Chamoun Z., Mann R.K., Nellen D., von Kessler D.P., Bellotto M.,
RA Beachy P.A., Basler K.;
RT "Skinny hedgehog, an acyltransferase required for palmitoylation and
RT activity of the hedgehog signal.";
RL Science 293:2080-2084(2001).
RN [10]
RP FUNCTION.
RX PubMed=11430830; DOI=10.1016/s1097-2765(01)00271-4;
RA Briscoe J., Chen Y., Jessell T.M., Struhl G.;
RT "A hedgehog-insensitive form of patched provides evidence for direct long-
RT range morphogen activity of sonic hedgehog in the neural tube.";
RL Mol. Cell 7:1279-1291(2001).
RN [11]
RP FUNCTION IN CEREBELLAR DEVELOPMENT.
RX PubMed=14687547; DOI=10.1016/s0896-6273(03)00769-4;
RA Gold D.A., Baek S.H., Schork N.J., Rose D.W., Larsen D.D., Sachs B.D.,
RA Rosenfeld M.G., Hamilton B.A.;
RT "RORalpha coordinates reciprocal signaling in cerebellar development
RT through sonic hedgehog and calcium-dependent pathways.";
RL Neuron 40:1119-1131(2003).
RN [12]
RP FUNCTION IN AXON GUIDANCE.
RX PubMed=12679031; DOI=10.1016/s0092-8674(03)00199-5;
RA Charron F., Stein E., Jeong J., McMahon A.P., Tessier-Lavigne M.;
RT "The morphogen sonic hedgehog is an axonal chemoattractant that
RT collaborates with netrin-1 in midline axon guidance.";
RL Cell 113:11-23(2003).
RN [13]
RP FUNCTION IN LIMB DEVELOPMENT.
RX PubMed=15315762; DOI=10.1016/j.cell.2004.07.023;
RA Ahn S., Joyner A.L.;
RT "Dynamic changes in the response of cells to positive hedgehog signaling
RT during mouse limb patterning.";
RL Cell 118:505-516(2004).
RN [14]
RP PALMITOYLATION AT CYS-25, MUTAGENESIS OF CYS-25, SUBUNIT, AND SUBCELLULAR
RP LOCATION.
RX PubMed=15075292; DOI=10.1101/gad.1185804;
RA Chen M.-H., Li Y.-J., Kawakami T., Xu S.-M., Chuang P.-T.;
RT "Palmitoylation is required for the production of a soluble multimeric
RT Hedgehog protein complex and long-range signaling in vertebrates.";
RL Genes Dev. 18:641-659(2004).
RN [15]
RP MUTAGENESIS OF GLY-32; ASP-89; GLN-101; ASN-116; TRP-118 AND GLU-189.
RX PubMed=16282375; DOI=10.1073/pnas.0507848102;
RA Maity T., Fuse N., Beachy P.A.;
RT "Molecular mechanisms of Sonic hedgehog mutant effects in
RT holoprosencephaly.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:17026-17031(2005).
RN [16]
RP INTERACTION WITH HHATL.
RX PubMed=18081866; DOI=10.1111/j.1742-4658.2007.06202.x;
RA Abe Y., Kita Y., Niikura T.;
RT "Mammalian Gup1, a homolog of Saccharomyces cerevisiae glycerol
RT uptake/transporter 1, acts as a negative regulator for N-terminal
RT palmitoylation of Sonic hedgehog.";
RL FEBS J. 275:318-331(2008).
RN [17]
RP INTERACTION WITH GPC3.
RX PubMed=18477453; DOI=10.1016/j.devcel.2008.03.006;
RA Capurro M.I., Xu P., Shi W., Li F., Jia A., Filmus J.;
RT "Glypican-3 inhibits Hedgehog signaling during development by competing
RT with patched for Hedgehog binding.";
RL Dev. Cell 14:700-711(2008).
RN [18]
RP REVIEW, AND FUNCTION.
RX PubMed=21357747; DOI=10.1083/jcb.201008090;
RA Chen X., Tukachinsky H., Huang C.H., Jao C., Chu Y.R., Tang H.Y.,
RA Mueller B., Schulman S., Rapoport T.A., Salic A.;
RT "Processing and turnover of the Hedgehog protein in the endoplasmic
RT reticulum.";
RL J. Cell Biol. 192:825-838(2011).
RN [19]
RP INTERACTION WITH DISP1 AND SCUBE2, SUBUNIT, AND CAUTION.
RX PubMed=22902404; DOI=10.1016/j.celrep.2012.07.010;
RA Tukachinsky H., Kuzmickas R.P., Jao C.Y., Liu J., Salic A.;
RT "Dispatched and scube mediate the efficient secretion of the cholesterol-
RT modified hedgehog ligand.";
RL Cell Rep. 2:308-320(2012).
RN [20]
RP INTERACTION WITH SCUBE2, SUBUNIT, AND CAUTION.
RX PubMed=22677548; DOI=10.1101/gad.191866.112;
RA Creanga A., Glenn T.D., Mann R.K., Saunders A.M., Talbot W.S., Beachy P.A.;
RT "Scube/You activity mediates release of dually lipid-modified Hedgehog
RT signal in soluble form.";
RL Genes Dev. 26:1312-1325(2012).
RN [21]
RP PTM, AND DOMAIN.
RX PubMed=23118222; DOI=10.1074/jbc.m112.356667;
RA Ohlig S., Pickhinke U., Sirko S., Bandari S., Hoffmann D., Dreier R.,
RA Farshi P., Goetz M., Grobe K.;
RT "An emerging role of Sonic hedgehog shedding as a modulator of heparan
RT sulfate interactions.";
RL J. Biol. Chem. 287:43708-43719(2012).
RN [22]
RP PTM, INTERACTION WITH SCUBE2, AND SUBUNIT.
RX PubMed=24522195; DOI=10.1242/jcs.137695;
RA Jakobs P., Exner S., Schuermann S., Pickhinke U., Bandari S., Ortmann C.,
RA Kupich S., Schulz P., Hansen U., Seidler D.G., Grobe K.;
RT "Scube2 enhances proteolytic Shh processing from the surface of Shh-
RT producing cells.";
RL J. Cell Sci. 127:1726-1737(2014).
RN [23]
RP REVIEW, AND FUNCTION.
RX PubMed=24863049; DOI=10.1002/dneu.22193;
RA Pal K., Mukhopadhyay S.;
RT "Primary cilium and sonic hedgehog signaling during neural tube patterning:
RT role of GPCRs and second messengers.";
RL Dev. Neurobiol. 75:337-348(2015).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 34-195 IN COMPLEX WITH ZINC IONS.
RX PubMed=7477329; DOI=10.1038/378212a0;
RA Hall T.M.T., Porter J.A., Beachy P.A., Leahy D.J.;
RT "A potential catalytic site revealed by the 1.7-A crystal structure of the
RT amino-terminal signalling domain of Sonic hedgehog.";
RL Nature 378:212-216(1995).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 26-189 IN COMPLEX WITH CDON;
RP CALCIUM AND ZINC IONS, DOMAIN, AND INTERACTION WITH CDON.
RX PubMed=18794898; DOI=10.1038/nature07358;
RA McLellan J.S., Zheng X., Hauk G., Ghirlando R., Beachy P.A., Leahy D.J.;
RT "The mode of Hedgehog binding to Ihog homologues is not conserved across
RT different phyla.";
RL Nature 455:979-983(2008).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (3.15 ANGSTROMS) OF 40-191 IN COMPLEX WITH HHIP;
RP CALCIUM AND ZINC IONS, DOMAIN, AND INTERACTION WITH HHIP.
RX PubMed=19561611; DOI=10.1038/nsmb.1607;
RA Bishop B., Aricescu A.R., Harlos K., O'Callaghan C.A., Jones E.Y.,
RA Siebold C.;
RT "Structural insights into hedgehog ligand sequestration by the human
RT hedgehog-interacting protein HHIP.";
RL Nat. Struct. Mol. Biol. 16:698-703(2009).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 26-189 IN COMPLEX WITH CALCIUM AND
RP ZINC IONS, DOMAIN, AND INTERACTION WITH BOC AND CDON.
RX PubMed=20519495; DOI=10.1074/jbc.m110.131680;
RA Kavran J.M., Ward M.D., Oladosu O.O., Mulepati S., Leahy D.J.;
RT "All mammalian Hedgehog proteins interact with cell adhesion molecule,
RT down-regulated by oncogenes (CDO) and brother of CDO (BOC) in a conserved
RT manner.";
RL J. Biol. Chem. 285:24584-24590(2010).
CC -!- FUNCTION: [Sonic hedgehog protein]: The C-terminal part of the sonic
CC hedgehog protein precursor displays an autoproteolysis and a
CC cholesterol transferase activity (PubMed:8824192, PubMed:7891723,
CC PubMed:7736596). Both activities result in the cleavage of the full-
CC length protein into two parts (ShhN and ShhC) followed by the covalent
CC attachment of a cholesterol moiety to the C-terminal of the newly
CC generated ShhN (PubMed:8824192). Both activities occur in the reticulum
CC endoplasmic (PubMed:21357747). Once cleaved, ShhC is degraded in the
CC endoplasmic reticulum (PubMed:21357747). {ECO:0000269|PubMed:7736596,
CC ECO:0000269|PubMed:7891723, ECO:0000269|PubMed:8824192,
CC ECO:0000305|PubMed:21357747}.
CC -!- FUNCTION: [Sonic hedgehog protein N-product]: The dually lipidated
CC sonic hedgehog protein N-product (ShhNp) is a morphogen which is
CC essential for a variety of patterning events during development.
CC Induces ventral cell fate in the neural tube and somites
CC (PubMed:11430830, PubMed:24863049). Involved in the patterning of the
CC anterior-posterior axis of the developing limb bud (PubMed:15315762).
CC Essential for axon guidance (PubMed:12679031). Binds to the patched
CC (PTCH1) receptor, which functions in association with smoothened (SMO),
CC to activate the transcription of target genes (By similarity). In the
CC absence of SHH, PTCH1 represses the constitutive signaling activity of
CC SMO (By similarity). {ECO:0000250|UniProtKB:Q15465,
CC ECO:0000269|PubMed:14687547, ECO:0000269|PubMed:7736596,
CC ECO:0000303|PubMed:24522195}.
CC -!- CATALYTIC ACTIVITY: [Sonic hedgehog protein]:
CC Reaction=cholesterol + glycyl-L-cysteinyl-[protein] + H(+) = [protein]-
CC C-terminal glycyl cholesterol ester + N-terminal L-cysteinyl-
CC [protein]; Xref=Rhea:RHEA:59504, Rhea:RHEA-COMP:12707, Rhea:RHEA-
CC COMP:15369, Rhea:RHEA-COMP:15374, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16113, ChEBI:CHEBI:65250, ChEBI:CHEBI:143135,
CC ChEBI:CHEBI:143140; Evidence={ECO:0000269|PubMed:8824192};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59505;
CC Evidence={ECO:0000269|PubMed:8824192};
CC -!- SUBUNIT: Interacts with HHATL/GUP1 which negatively regulates HHAT-
CC mediated palmitoylation of the SHH N-terminus (PubMed:18081866).
CC Interacts with BOC and CDON (PubMed:18794898). Interacts with HHIP (By
CC similarity). Interacts with DISP1 via its cholesterol anchor
CC (PubMed:22902404, PubMed:22677548). Interacts with SCUBE2
CC (PubMed:24522195, PubMed:22677548). Interacts with glypican GPC3
CC (PubMed:18477453). {ECO:0000250|UniProtKB:Q15465,
CC ECO:0000269|PubMed:15075292, ECO:0000269|PubMed:18081866,
CC ECO:0000269|PubMed:18477453, ECO:0000269|PubMed:18794898,
CC ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495,
CC ECO:0000269|PubMed:22677548, ECO:0000269|PubMed:7477329}.
CC -!- SUBUNIT: [Sonic hedgehog protein N-product]: Multimer.
CC {ECO:0000269|PubMed:24522195}.
CC -!- INTERACTION:
CC Q62226; Q4KMG0: CDON; Xeno; NbExp=7; IntAct=EBI-15610166, EBI-7016840;
CC Q62226; Q96QV1-1: HHIP; Xeno; NbExp=4; IntAct=EBI-15610166, EBI-15791478;
CC -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein]: Endoplasmic reticulum
CC membrane {ECO:0000250|UniProtKB:Q15465}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q15465}. Note=Co-localizes with HHAT in the ER
CC and Golgi membrane. {ECO:0000250|UniProtKB:Q15465}.
CC -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein N-product]: Cell membrane
CC {ECO:0000269|PubMed:7891723}; Lipid-anchor
CC {ECO:0000269|PubMed:7891723}. Note=The dual-lipidated sonic hedgehog
CC protein N-product (ShhNp) is firmly tethered to the cell membrane where
CC it forms multimers (PubMed:24522195). Further solubilization and
CC release from the cell surface seem to be achieved through different
CC mechanisms, including the interaction with DISP1 and SCUBE2, movement
CC by lipoprotein particles, transport by cellular extensions called
CC cytonemes or by the proteolytic removal of both terminal lipidated
CC peptides. {ECO:0000269|PubMed:24522195, ECO:0000305|PubMed:22677548}.
CC -!- TISSUE SPECIFICITY: Expressed in a number of embryonic tissues
CC including the notochord, ventral neural tube, floor plate, lung bud,
CC zone of polarizing activity and posterior distal mesenchyme of limbs.
CC In the adult, expressed in lung and neural retina.
CC -!- DEVELOPMENTAL STAGE: First detectable during gastrulation.
CC -!- INDUCTION: By retinoic acid.
CC -!- DOMAIN: [Sonic hedgehog protein N-product]: Binds calcium and zinc
CC ions; this stabilizes the protein fold and is essential for protein-
CC protein interactions mediated by this domain.
CC {ECO:0000269|PubMed:18794898, ECO:0000269|PubMed:19561611,
CC ECO:0000269|PubMed:20519495}.
CC -!- DOMAIN: [Sonic hedgehog protein N-product]: The Cardin-Weintraub (CW)
CC motif is required for heparan sulfate binding of the solubilized ShhNp
CC (PubMed:23118222). The N-terminal palmitoylated peptide is cleaved at
CC the heparan sulfate-binding Cardin-Weintraub (CW) motif site
CC (PubMed:24522195). The cleavage reduced the interactions with heparan
CC sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195).
CC {ECO:0000269|PubMed:23118222, ECO:0000269|PubMed:24522195}.
CC -!- PTM: [Sonic hedgehog protein]: The C-terminal domain displays an
CC autoproteolysis activity and a cholesterol transferase activity
CC (PubMed:7891723, PubMed:7736596, PubMed:8824192). Both activities
CC result in the cleavage of the full-length protein and covalent
CC attachment of a cholesterol moiety to the C-terminal of the newly
CC generated N-terminal fragment (ShhN)(PubMed:7891723, PubMed:7736596,
CC PubMed:8824192). Cholesterylation is required for the sonic hedgehog
CC protein N-product targeting to lipid rafts and multimerization
CC (PubMed:24522195, PubMed:8824192). ShhN is the active species in both
CC local and long-range signaling, whereas the C-product (ShhC) is
CC degraded in the reticulum endoplasmic (PubMed:21357747).
CC {ECO:0000269|PubMed:7720571, ECO:0000269|PubMed:7736596,
CC ECO:0000269|PubMed:7891723, ECO:0000269|PubMed:8824192,
CC ECO:0000305|PubMed:21357747, ECO:0000305|PubMed:24522195}.
CC -!- PTM: [Sonic hedgehog protein N-product]: N-palmitoylation by HHAT of
CC ShhN is required for sonic hedgehog protein N-product multimerization
CC and full activity (PubMed:11486055, PubMed:15075292). It is a
CC prerequisite for the membrane-proximal positioning and the subsequent
CC shedding of this N-terminal peptide (PubMed:24522195).
CC {ECO:0000269|PubMed:11486055, ECO:0000269|PubMed:15075292,
CC ECO:0000269|PubMed:24522195}.
CC -!- PTM: [Sonic hedgehog protein N-product]: The lipidated N- and C-
CC terminal peptides of ShhNp can be cleaved (shedding)(PubMed:24522195).
CC The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub
CC (CW) motif site (PubMed:24522195). The cleavage reduced the
CC interactions with heparan sulfate (PubMed:23118222). The cleavage is
CC enhanced by SCUBE2. {ECO:0000269|PubMed:23118222,
CC ECO:0000269|PubMed:24522195}.
CC -!- MISCELLANEOUS: Mice overexpressing Shh display digit duplications in
CC both forelimbs and hindlimbs. {ECO:0000269|PubMed:15315762}.
CC -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}.
CC -!- CAUTION: The several steps and mechanisms that permit controlled Shh
CC dispersion and gradient formation remain controversial. The ShhNC C-
CC terminal domain displays an autoproteolysis activity and a cholesterol
CC transferase activity resulting in the cleavage and covalent attachment
CC of a cholesterol moiety to the C-terminal of the newly generated N-
CC terminal fragment (ShhN). The protein is further modified by covalent
CC addition of palmitate at the N-terminal of ShhN, resulting to the dual-
CC lipidated Shh (ShhNp). ShhNp is firmly tethered to the cell membrane
CC where it forms multimers. Further solubilization and release from the
CC cell surface seem to be achieved through different mechanisms,
CC including the interaction with DISP1 and SCUBE2, movement by
CC lipoprotein particles, transport by cellular extensions called
CC cytonemes or by proteolytic removal of both terminal lipidated
CC peptides. Once released, the fully processed Shh can signal within
CC embryonic tissues both at short and long-range.
CC {ECO:0000269|PubMed:24522195, ECO:0000305|PubMed:22677548,
CC ECO:0000305|PubMed:22902404}.
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DR EMBL; X76290; CAA53922.1; -; mRNA.
DR EMBL; AK077688; BAC36956.1; -; mRNA.
DR EMBL; BC063087; AAH63087.1; -; mRNA.
DR CCDS; CCDS19146.1; -.
DR PIR; A49425; A49425.
DR RefSeq; NP_033196.1; NM_009170.3.
DR PDB; 1VHH; X-ray; 1.70 A; A=34-195.
DR PDB; 2WFX; X-ray; 3.20 A; A=40-191.
DR PDB; 2WG4; X-ray; 3.15 A; A=40-191.
DR PDB; 3D1M; X-ray; 1.70 A; A/B=26-189.
DR PDB; 3N1R; X-ray; 2.13 A; A=40-195.
DR PDB; 4C4M; X-ray; 1.74 A; A=40-195.
DR PDB; 4C4N; X-ray; 2.36 A; A/B=40-195.
DR PDB; 7RPK; EM; 2.70 A; H=26-189.
DR PDBsum; 1VHH; -.
DR PDBsum; 2WFX; -.
DR PDBsum; 2WG4; -.
DR PDBsum; 3D1M; -.
DR PDBsum; 3N1R; -.
DR PDBsum; 4C4M; -.
DR PDBsum; 4C4N; -.
DR PDBsum; 7RPK; -.
DR AlphaFoldDB; Q62226; -.
DR SMR; Q62226; -.
DR BioGRID; 203220; 10.
DR DIP; DIP-48537N; -.
DR IntAct; Q62226; 7.
DR STRING; 10090.ENSMUSP00000002708; -.
DR BindingDB; Q62226; -.
DR ChEMBL; CHEMBL5387; -.
DR DrugCentral; Q62226; -.
DR MEROPS; C46.002; -.
DR GlyGen; Q62226; 1 site.
DR iPTMnet; Q62226; -.
DR PhosphoSitePlus; Q62226; -.
DR SwissPalm; Q62226; -.
DR MaxQB; Q62226; -.
DR PaxDb; Q62226; -.
DR PRIDE; Q62226; -.
DR ProteomicsDB; 261352; -.
DR ABCD; Q62226; 3 sequenced antibodies.
DR Antibodypedia; 4514; 596 antibodies from 41 providers.
DR DNASU; 20423; -.
DR Ensembl; ENSMUST00000002708; ENSMUSP00000002708; ENSMUSG00000002633.
DR GeneID; 20423; -.
DR KEGG; mmu:20423; -.
DR UCSC; uc008wua.2; mouse.
DR CTD; 6469; -.
DR MGI; MGI:98297; Shh.
DR VEuPathDB; HostDB:ENSMUSG00000002633; -.
DR eggNOG; KOG3638; Eukaryota.
DR GeneTree; ENSGT00940000159119; -.
DR HOGENOM; CLU_034686_0_0_1; -.
DR InParanoid; Q62226; -.
DR OMA; LDSHSIH; -.
DR OrthoDB; 1169356at2759; -.
DR PhylomeDB; Q62226; -.
DR TreeFam; TF106458; -.
DR Reactome; R-MMU-5358346; Hedgehog ligand biogenesis.
DR Reactome; R-MMU-5362798; Release of Hh-Np from the secreting cell.
DR Reactome; R-MMU-5632681; Ligand-receptor interactions.
DR Reactome; R-MMU-5635838; Activation of SMO.
DR BioGRID-ORCS; 20423; 1 hit in 78 CRISPR screens.
DR EvolutionaryTrace; Q62226; -.
DR PRO; PR:Q62226; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q62226; protein.
DR Bgee; ENSMUSG00000002633; Expressed in urinary bladder urothelium and 292 other tissues.
DR Genevisible; Q62226; MM.
DR GO; GO:0030424; C:axon; ISO:MGI.
DR GO; GO:0009986; C:cell surface; IDA:MGI.
DR GO; GO:0030425; C:dendrite; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031012; C:extracellular matrix; IDA:MGI.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:MGI.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0045121; C:membrane raft; IDA:MGI.
DR GO; GO:0043025; C:neuronal cell body; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0008021; C:synaptic vesicle; ISO:MGI.
DR GO; GO:0030133; C:transport vesicle; ISO:MGI.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0005539; F:glycosaminoglycan binding; IDA:MGI.
DR GO; GO:0043237; F:laminin-1 binding; IDA:MGI.
DR GO; GO:0005113; F:patched binding; IPI:Roslin.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0046632; P:alpha-beta T cell differentiation; IMP:MGI.
DR GO; GO:0048856; P:anatomical structure development; IMP:MGI.
DR GO; GO:0048646; P:anatomical structure formation involved in morphogenesis; IMP:MGI.
DR GO; GO:0008209; P:androgen metabolic process; IMP:MGI.
DR GO; GO:0001525; P:angiogenesis; IDA:MGI.
DR GO; GO:0048645; P:animal organ formation; IMP:MGI.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IMP:MGI.
DR GO; GO:0097190; P:apoptotic signaling pathway; IDA:Roslin.
DR GO; GO:0060840; P:artery development; IMP:MGI.
DR GO; GO:0048708; P:astrocyte differentiation; IMP:MGI.
DR GO; GO:0007411; P:axon guidance; IDA:MGI.
DR GO; GO:0060020; P:Bergmann glial cell differentiation; IDA:MGI.
DR GO; GO:0007596; P:blood coagulation; IMP:MGI.
DR GO; GO:0001569; P:branching involved in blood vessel morphogenesis; IMP:MGI.
DR GO; GO:0060442; P:branching involved in prostate gland morphogenesis; IDA:MGI.
DR GO; GO:0060445; P:branching involved in salivary gland morphogenesis; IMP:MGI.
DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; IMP:MGI.
DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; IMP:MGI.
DR GO; GO:0060447; P:bud outgrowth involved in lung branching; IMP:MGI.
DR GO; GO:0043010; P:camera-type eye development; IDA:MGI.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IMP:MGI.
DR GO; GO:0043369; P:CD4-positive or CD8-positive, alpha-beta T cell lineage commitment; IMP:BHF-UCL.
DR GO; GO:0048468; P:cell development; IMP:MGI.
DR GO; GO:0045165; P:cell fate commitment; IGI:MGI.
DR GO; GO:0001708; P:cell fate specification; IDA:MGI.
DR GO; GO:0016477; P:cell migration; IDA:MGI.
DR GO; GO:0008283; P:cell population proliferation; IMP:MGI.
DR GO; GO:0021924; P:cell proliferation in external granule layer; IDA:MGI.
DR GO; GO:0007267; P:cell-cell signaling; IMP:MGI.
DR GO; GO:0071285; P:cellular response to lithium ion; IDA:MGI.
DR GO; GO:0007417; P:central nervous system development; IMP:MGI.
DR GO; GO:0021930; P:cerebellar granule cell precursor proliferation; IDA:UniProtKB.
DR GO; GO:0071679; P:commissural neuron axon guidance; ISO:MGI.
DR GO; GO:0003140; P:determination of left/right asymmetry in lateral mesoderm; IMP:BHF-UCL.
DR GO; GO:0007368; P:determination of left/right symmetry; IMP:MGI.
DR GO; GO:0048589; P:developmental growth; IMP:MGI.
DR GO; GO:0007502; P:digestive tract mesoderm development; ISO:MGI.
DR GO; GO:0048546; P:digestive tract morphogenesis; IMP:MGI.
DR GO; GO:0071542; P:dopaminergic neuron differentiation; TAS:ParkinsonsUK-UCL.
DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IDA:MGI.
DR GO; GO:0009953; P:dorsal/ventral pattern formation; IGI:MGI.
DR GO; GO:0007398; P:ectoderm development; IMP:MGI.
DR GO; GO:0048557; P:embryonic digestive tract morphogenesis; IMP:MGI.
DR GO; GO:0042733; P:embryonic digit morphogenesis; IMP:Roslin.
DR GO; GO:0048617; P:embryonic foregut morphogenesis; IMP:MGI.
DR GO; GO:0035115; P:embryonic forelimb morphogenesis; IMP:MGI.
DR GO; GO:0035116; P:embryonic hindlimb morphogenesis; IMP:MGI.
DR GO; GO:0030326; P:embryonic limb morphogenesis; IMP:MGI.
DR GO; GO:0048598; P:embryonic morphogenesis; IMP:MGI.
DR GO; GO:0048568; P:embryonic organ development; IMP:MGI.
DR GO; GO:0048706; P:embryonic skeletal system development; IGI:MGI.
DR GO; GO:0006897; P:endocytosis; IDA:MGI.
DR GO; GO:0050673; P:epithelial cell proliferation; IMP:MGI.
DR GO; GO:0060767; P:epithelial cell proliferation involved in prostate gland development; IMP:MGI.
DR GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; IMP:MGI.
DR GO; GO:0060441; P:epithelial tube branching involved in lung morphogenesis; IMP:MGI.
DR GO; GO:0060684; P:epithelial-mesenchymal cell signaling; IMP:MGI.
DR GO; GO:0060738; P:epithelial-mesenchymal signaling involved in prostate gland development; IGI:MGI.
DR GO; GO:0090162; P:establishment of epithelial cell polarity; IDA:MGI.
DR GO; GO:0030900; P:forebrain development; IGI:MGI.
DR GO; GO:0021871; P:forebrain regionalization; IMP:MGI.
DR GO; GO:0048859; P:formation of anatomical boundary; IMP:MGI.
DR GO; GO:0061196; P:fungiform papilla development; ISO:MGI.
DR GO; GO:0061198; P:fungiform papilla formation; ISO:MGI.
DR GO; GO:0061197; P:fungiform papilla morphogenesis; ISO:MGI.
DR GO; GO:0010467; P:gene expression; IMP:MGI.
DR GO; GO:0001942; P:hair follicle development; IMP:MGI.
DR GO; GO:0031069; P:hair follicle morphogenesis; IMP:MGI.
DR GO; GO:0007507; P:heart development; IMP:MGI.
DR GO; GO:0001947; P:heart looping; IMP:BHF-UCL.
DR GO; GO:0030902; P:hindbrain development; IMP:MGI.
DR GO; GO:0007442; P:hindgut morphogenesis; IMP:MGI.
DR GO; GO:0048839; P:inner ear development; IMP:MGI.
DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro.
DR GO; GO:0045109; P:intermediate filament organization; IMP:MGI.
DR GO; GO:0001822; P:kidney development; IMP:MGI.
DR GO; GO:0060459; P:left lung development; IMP:MGI.
DR GO; GO:0060174; P:limb bud formation; IMP:MGI.
DR GO; GO:0060173; P:limb development; IMP:MGI.
DR GO; GO:0030324; P:lung development; IMP:MGI.
DR GO; GO:0060428; P:lung epithelium development; IMP:MGI.
DR GO; GO:0060463; P:lung lobe morphogenesis; IMP:MGI.
DR GO; GO:0060425; P:lung morphogenesis; IMP:MGI.
DR GO; GO:0060484; P:lung-associated mesenchyme development; IMP:MGI.
DR GO; GO:0002320; P:lymphoid progenitor cell differentiation; IMP:BHF-UCL.
DR GO; GO:0030539; P:male genitalia development; IMP:MGI.
DR GO; GO:0048808; P:male genitalia morphogenesis; ISO:MGI.
DR GO; GO:0097152; P:mesenchymal cell apoptotic process; IMP:MGI.
DR GO; GO:0010463; P:mesenchymal cell proliferation; IMP:MGI.
DR GO; GO:0060916; P:mesenchymal cell proliferation involved in lung development; IDA:MGI.
DR GO; GO:0060783; P:mesenchymal smoothened signaling pathway involved in prostate gland development; IMP:MGI.
DR GO; GO:0072205; P:metanephric collecting duct development; IEA:Ensembl.
DR GO; GO:0072136; P:metanephric mesenchymal cell proliferation involved in metanephros development; IMP:UniProtKB.
DR GO; GO:0001656; P:metanephros development; IMP:UniProtKB.
DR GO; GO:0030901; P:midbrain development; IGI:MGI.
DR GO; GO:0045445; P:myoblast differentiation; IDA:MGI.
DR GO; GO:0014902; P:myotube differentiation; IMP:MGI.
DR GO; GO:0046639; P:negative regulation of alpha-beta T cell differentiation; IMP:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:Roslin.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:MGI.
DR GO; GO:0030336; P:negative regulation of cell migration; IDA:MGI.
DR GO; GO:0090370; P:negative regulation of cholesterol efflux; IMP:BHF-UCL.
DR GO; GO:1904339; P:negative regulation of dopaminergic neuron differentiation; IMP:ParkinsonsUK-UCL.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:UniProtKB.
DR GO; GO:2000357; P:negative regulation of kidney smooth muscle cell differentiation; IDA:UniProtKB.
DR GO; GO:2001054; P:negative regulation of mesenchymal cell apoptotic process; IMP:MGI.
DR GO; GO:1901215; P:negative regulation of neuron death; ISO:MGI.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IDA:MGI.
DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:MGI.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IMP:MGI.
DR GO; GO:0033085; P:negative regulation of T cell differentiation in thymus; IMP:MGI.
DR GO; GO:0042130; P:negative regulation of T cell proliferation; IMP:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; IDA:MGI.
DR GO; GO:2000062; P:negative regulation of ureter smooth muscle cell differentiation; IDA:UniProtKB.
DR GO; GO:0030178; P:negative regulation of Wnt signaling pathway; IDA:MGI.
DR GO; GO:0045060; P:negative thymic T cell selection; IMP:BHF-UCL.
DR GO; GO:0001755; P:neural crest cell migration; IMP:MGI.
DR GO; GO:0001841; P:neural tube formation; ISO:MGI.
DR GO; GO:0007405; P:neuroblast proliferation; IDA:MGI.
DR GO; GO:0030182; P:neuron differentiation; IDA:MGI.
DR GO; GO:0048663; P:neuron fate commitment; IMP:MGI.
DR GO; GO:0042476; P:odontogenesis; IDA:MGI.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IMP:MGI.
DR GO; GO:0014003; P:oligodendrocyte development; IDA:MGI.
DR GO; GO:0048709; P:oligodendrocyte differentiation; IGI:MGI.
DR GO; GO:0002076; P:osteoblast development; IDA:MGI.
DR GO; GO:0031016; P:pancreas development; IMP:MGI.
DR GO; GO:0007389; P:pattern specification process; IMP:MGI.
DR GO; GO:0009949; P:polarity specification of anterior/posterior axis; IMP:Roslin.
DR GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; IMP:BHF-UCL.
DR GO; GO:0048711; P:positive regulation of astrocyte differentiation; IMP:MGI.
DR GO; GO:0051781; P:positive regulation of cell division; ISO:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:MGI.
DR GO; GO:0021940; P:positive regulation of cerebellar granule cell precursor proliferation; IDA:MGI.
DR GO; GO:2001028; P:positive regulation of endothelial cell chemotaxis; ISO:MGI.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IMP:MGI.
DR GO; GO:0060769; P:positive regulation of epithelial cell proliferation involved in prostate gland development; IMP:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0007228; P:positive regulation of hh target transcription factor activity; IDA:MGI.
DR GO; GO:0033092; P:positive regulation of immature T cell proliferation in thymus; IMP:BHF-UCL.
DR GO; GO:2000358; P:positive regulation of kidney smooth muscle cell differentiation; IDA:UniProtKB.
DR GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; IMP:MGI.
DR GO; GO:2000729; P:positive regulation of mesenchymal cell proliferation involved in ureter development; IMP:UniProtKB.
DR GO; GO:0002052; P:positive regulation of neuroblast proliferation; IDA:MGI.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; ISO:MGI.
DR GO; GO:0032901; P:positive regulation of neurotrophin production; ISO:MGI.
DR GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; IDA:MGI.
DR GO; GO:0070447; P:positive regulation of oligodendrocyte progenitor proliferation; ISO:MGI.
DR GO; GO:0060406; P:positive regulation of penile erection; ISO:MGI.
DR GO; GO:0046534; P:positive regulation of photoreceptor cell differentiation; ISO:MGI.
DR GO; GO:0042307; P:positive regulation of protein import into nucleus; IGI:MGI.
DR GO; GO:0061189; P:positive regulation of sclerotome development; ISO:MGI.
DR GO; GO:0014858; P:positive regulation of skeletal muscle cell proliferation; IMP:MGI.
DR GO; GO:0048643; P:positive regulation of skeletal muscle tissue development; IMP:MGI.
DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IMP:BHF-UCL.
DR GO; GO:1903672; P:positive regulation of sprouting angiogenesis; ISO:MGI.
DR GO; GO:0051155; P:positive regulation of striated muscle cell differentiation; IMP:MGI.
DR GO; GO:0033089; P:positive regulation of T cell differentiation in thymus; IMP:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:2000063; P:positive regulation of ureter smooth muscle cell differentiation; IMP:UniProtKB.
DR GO; GO:0030177; P:positive regulation of Wnt signaling pathway; IMP:MGI.
DR GO; GO:0045059; P:positive thymic T cell selection; IMP:BHF-UCL.
DR GO; GO:0060516; P:primary prostatic bud elongation; IDA:MGI.
DR GO; GO:0060523; P:prostate epithelial cord elongation; IDA:MGI.
DR GO; GO:0030850; P:prostate gland development; IMP:MGI.
DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR GO; GO:0006606; P:protein import into nucleus; IGI:MGI.
DR GO; GO:0034504; P:protein localization to nucleus; IDA:MGI.
DR GO; GO:0042127; P:regulation of cell population proliferation; ISO:MGI.
DR GO; GO:0060768; P:regulation of epithelial cell proliferation involved in prostate gland development; IMP:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IDA:MGI.
DR GO; GO:0060251; P:regulation of glial cell proliferation; IDA:MGI.
DR GO; GO:0060782; P:regulation of mesenchymal cell proliferation involved in prostate gland development; IMP:MGI.
DR GO; GO:0042481; P:regulation of odontogenesis; IMP:BHF-UCL.
DR GO; GO:0060685; P:regulation of prostatic bud formation; IDA:MGI.
DR GO; GO:1900180; P:regulation of protein localization to nucleus; ISO:MGI.
DR GO; GO:0030162; P:regulation of proteolysis; IDA:MGI.
DR GO; GO:0072091; P:regulation of stem cell proliferation; IMP:MGI.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IMP:MGI.
DR GO; GO:0030323; P:respiratory tube development; IMP:MGI.
DR GO; GO:0048678; P:response to axon injury; ISO:MGI.
DR GO; GO:0045471; P:response to ethanol; ISO:MGI.
DR GO; GO:0060458; P:right lung development; IMP:MGI.
DR GO; GO:0060021; P:roof of mouth development; IMP:MGI.
DR GO; GO:0060662; P:salivary gland cavitation; IDA:MGI.
DR GO; GO:0007165; P:signal transduction; TAS:MGI.
DR GO; GO:0014856; P:skeletal muscle cell proliferation; IMP:MGI.
DR GO; GO:0098528; P:skeletal muscle fiber differentiation; IMP:MGI.
DR GO; GO:0007519; P:skeletal muscle tissue development; IMP:MGI.
DR GO; GO:0043588; P:skin development; IMP:MGI.
DR GO; GO:0048745; P:smooth muscle tissue development; IEA:Ensembl.
DR GO; GO:0007224; P:smoothened signaling pathway; IDA:MGI.
DR GO; GO:0021938; P:smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation; IDA:MGI.
DR GO; GO:0061053; P:somite development; IMP:BHF-UCL.
DR GO; GO:0021513; P:spinal cord dorsal/ventral patterning; IMP:MGI.
DR GO; GO:0021522; P:spinal cord motor neuron differentiation; IGI:MGI.
DR GO; GO:0048864; P:stem cell development; IMP:BHF-UCL.
DR GO; GO:0072089; P:stem cell proliferation; IDA:MGI.
DR GO; GO:0051146; P:striated muscle cell differentiation; IDA:MGI.
DR GO; GO:0014706; P:striated muscle tissue development; IMP:MGI.
DR GO; GO:0033077; P:T cell differentiation in thymus; IMP:BHF-UCL.
DR GO; GO:0042098; P:T cell proliferation; IMP:MGI.
DR GO; GO:0021978; P:telencephalon regionalization; IMP:MGI.
DR GO; GO:0021794; P:thalamus development; IMP:MGI.
DR GO; GO:0048538; P:thymus development; IMP:BHF-UCL.
DR GO; GO:0030878; P:thyroid gland development; IMP:MGI.
DR GO; GO:0043586; P:tongue development; ISO:MGI.
DR GO; GO:0043587; P:tongue morphogenesis; ISO:MGI.
DR GO; GO:0060438; P:trachea development; IMP:MGI.
DR GO; GO:0060439; P:trachea morphogenesis; IMP:MGI.
DR GO; GO:1905327; P:tracheoesophageal septum formation; IMP:MGI.
DR GO; GO:0036484; P:trunk neural crest cell migration; IDA:MGI.
DR GO; GO:0001944; P:vasculature development; IMP:MGI.
DR GO; GO:0001570; P:vasculogenesis; IDA:MGI.
DR GO; GO:0060979; P:vasculogenesis involved in coronary vascular morphogenesis; TAS:DFLAT.
DR GO; GO:0021521; P:ventral spinal cord interneuron specification; ISO:MGI.
DR GO; GO:0022006; P:zona limitans intrathalamica formation; ISO:MGI.
DR Gene3D; 3.30.1380.10; -; 1.
DR InterPro; IPR001657; Hedgehog.
DR InterPro; IPR001767; Hedgehog_Hint.
DR InterPro; IPR009045; Hedgehog_sig/DD-Pept_Zn-bd_sf.
DR InterPro; IPR000320; Hedgehog_signalling_dom.
DR InterPro; IPR003586; Hint_dom_C.
DR InterPro; IPR003587; Hint_dom_N.
DR InterPro; IPR036844; Hint_dom_sf.
DR InterPro; IPR006141; Intein_N.
DR Pfam; PF01085; HH_signal; 1.
DR Pfam; PF01079; Hint; 1.
DR PIRSF; PIRSF009400; Peptidase_C46; 1.
DR PRINTS; PR00632; SONICHHOG.
DR SMART; SM00305; HintC; 1.
DR SMART; SM00306; HintN; 1.
DR SUPFAM; SSF51294; SSF51294; 1.
DR SUPFAM; SSF55166; SSF55166; 1.
DR PROSITE; PS50817; INTEIN_N_TER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Autocatalytic cleavage; Calcium; Cell membrane;
KW Developmental protein; Endoplasmic reticulum; Glycoprotein;
KW Golgi apparatus; Hydrolase; Lipoprotein; Membrane; Metal-binding;
KW Palmitate; Protease; Reference proteome; Signal; Zinc.
FT SIGNAL 1..24
FT /evidence="ECO:0000250|UniProtKB:Q15465"
FT CHAIN 25..437
FT /note="Sonic hedgehog protein"
FT /id="PRO_0000013211"
FT CHAIN 25..198
FT /note="Sonic hedgehog protein N-product"
FT /id="PRO_0000013212"
FT MOTIF 33..39
FT /note="Cardin-Weintraub"
FT /evidence="ECO:0000269|PubMed:23118222"
FT BINDING 90
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495"
FT BINDING 91
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495"
FT BINDING 91
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495"
FT BINDING 96
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495"
FT BINDING 126
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495"
FT BINDING 127
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495"
FT BINDING 127
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495"
FT BINDING 130
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495"
FT BINDING 132
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495"
FT BINDING 141
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495,
FT ECO:0000269|PubMed:7477329"
FT BINDING 148
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495,
FT ECO:0000269|PubMed:7477329"
FT BINDING 183
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:18794898,
FT ECO:0000269|PubMed:19561611, ECO:0000269|PubMed:20519495,
FT ECO:0000269|PubMed:7477329"
FT SITE 198..199
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 244
FT /note="Involved in cholesterol transfer"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 268
FT /note="Involved in auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT SITE 271
FT /note="Essential for auto-cleavage"
FT /evidence="ECO:0000250|UniProtKB:Q02936"
FT LIPID 25
FT /note="N-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:11486055,
FT ECO:0000269|PubMed:15075292"
FT LIPID 198
FT /note="Cholesterol glycine ester"
FT /evidence="ECO:0000269|PubMed:8824192"
FT CARBOHYD 279
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT MUTAGEN 25
FT /note="C->S: Strongly reduces effects of in vivo
FT overexpression; impairs multimer formation; does not affect
FT subcellular location to lipid rafts. Homozygous mice are
FT characterized by a smaller size and holoprosencephaly at
FT 10.5 dpc, and shortening of limbs at 13.5 dpc. They die
FT soon after birth."
FT /evidence="ECO:0000269|PubMed:11486055,
FT ECO:0000269|PubMed:15075292, ECO:0000269|PubMed:23118222"
FT MUTAGEN 32
FT /note="G->R: Introduces a cleavage site for a furin-like
FT protease resulting in abnormal protein processing; cleavage
FT at this site removes 11 amino acids from the N-terminal
FT domain and reduces affinity of Shh for Ptch1 and signaling
FT potency in assays using chicken embryo neural plate
FT explants and mouse C3H10T1/2 stem cells."
FT /evidence="ECO:0000269|PubMed:16282375"
FT MUTAGEN 89
FT /note="D->V: Moderately reduces Ptch1 binding in vitro and
FT signaling potency in chicken embryo neural plate explant
FT assays compared with wild-type sequence."
FT /evidence="ECO:0000269|PubMed:16282375"
FT MUTAGEN 101
FT /note="Q->H: Does not affect signaling activity in any of
FT Shh signaling assays and causes no apparent defects in
FT cholesterol-mediated autoprocessing reactions."
FT /evidence="ECO:0000269|PubMed:16282375"
FT MUTAGEN 116
FT /note="N->K: Shows no change in activities at different
FT temperatures."
FT /evidence="ECO:0000269|PubMed:16282375"
FT MUTAGEN 118
FT /note="W->G: Causes a failure of Shh processing leading to
FT retention of the immature glycosylated protein within the
FT endoplasmic reticulum of transfected cells; causes a
FT temperature-dependent conformational change that allows Shh
FT to bind Ptch1 at 4 or 32 degrees Celsius but not at 37
FT degrees Celsius; drastically reduces signaling potency in
FT chicken embryo neural plate explant assays."
FT /evidence="ECO:0000269|PubMed:16282375"
FT MUTAGEN 118
FT /note="W->R: Causes a failure of Shh processing leading to
FT retention of the immature glycosylated protein within the
FT endoplasmic reticulum of transfected cells; causes a
FT temperature-dependent conformational change that allows Shh
FT to bind Ptch1 at 4 or 32 degrees Celsius but not at 37
FT degrees Celsius; drastically reduces signaling potency in
FT chicken embryo neural plate explant assays."
FT /evidence="ECO:0000269|PubMed:16282375"
FT MUTAGEN 189
FT /note="E->Q: Does not affect signaling activity in any of
FT Shh signaling assays and causes no apparent defects in
FT cholesterol-mediated autoprocessing reactions."
FT /evidence="ECO:0000269|PubMed:16282375"
FT STRAND 48..52
FT /evidence="ECO:0007829|PDB:1VHH"
FT TURN 57..60
FT /evidence="ECO:0007829|PDB:1VHH"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:3N1R"
FT HELIX 72..76
FT /evidence="ECO:0007829|PDB:1VHH"
FT STRAND 85..87
FT /evidence="ECO:0007829|PDB:1VHH"
FT STRAND 92..94
FT /evidence="ECO:0007829|PDB:1VHH"
FT HELIX 95..97
FT /evidence="ECO:0007829|PDB:1VHH"
FT HELIX 101..117
FT /evidence="ECO:0007829|PDB:1VHH"
FT STRAND 123..127
FT /evidence="ECO:0007829|PDB:1VHH"
FT STRAND 131..135
FT /evidence="ECO:0007829|PDB:2WG4"
FT HELIX 140..143
FT /evidence="ECO:0007829|PDB:1VHH"
FT STRAND 146..151
FT /evidence="ECO:0007829|PDB:1VHH"
FT HELIX 156..158
FT /evidence="ECO:0007829|PDB:1VHH"
FT HELIX 159..168
FT /evidence="ECO:0007829|PDB:1VHH"
FT STRAND 172..178
FT /evidence="ECO:0007829|PDB:1VHH"
FT STRAND 181..185
FT /evidence="ECO:0007829|PDB:1VHH"
FT HELIX 189..192
FT /evidence="ECO:0007829|PDB:1VHH"
SQ SEQUENCE 437 AA; 47773 MW; D0EB72F08E7860EF CRC64;
MLLLLARCFL VILASSLLVC PGLACGPGRG FGKRRHPKKL TPLAYKQFIP NVAEKTLGAS
GRYEGKITRN SERFKELTPN YNPDIIFKDE ENTGADRLMT QRCKDKLNAL AISVMNQWPG
VKLRVTEGWD EDGHHSEESL HYEGRAVDIT TSDRDRSKYG MLARLAVEAG FDWVYYESKA
HIHCSVKAEN SVAAKSGGCF PGSATVHLEQ GGTKLVKDLR PGDRVLAADD QGRLLYSDFL
TFLDRDEGAK KVFYVIETLE PRERLLLTAA HLLFVAPHND SGPTPGPSAL FASRVRPGQR
VYVVAERGGD RRLLPAAVHS VTLREEEAGA YAPLTAHGTI LINRVLASCY AVIEEHSWAH
RAFAPFRLAH ALLAALAPAR TDGGGGGSIP AAQSATEARG AEPTAGIHWY SQLLYHIGTW
LLDSETMHPL GMAVKSS
