ID IHH_MOUSE Reviewed; 411 AA. AC P97812; Q61724; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 15-JUL-1999, sequence version 2. DT 27-MAR-2024, entry version 199. DE RecName: Full=Indian hedgehog protein {ECO:0000305}; DE Short=IHH; DE EC=3.1.-.- {ECO:0000250|UniProtKB:Q62226}; DE AltName: Full=HHG-2; DE Contains: DE RecName: Full=Indian hedgehog protein N-product; DE Flags: Precursor; GN Name=Ihh {ECO:0000312|MGI:MGI:96533}; 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], PROTEOLYTIC PROCESSING, DEVELOPMENTAL STAGE, RP TISSUE SPECIFICITY, AND AUTOCATALYTIC CLEAVAGE. RC STRAIN=CD-1; TISSUE=Kidney; RX PubMed=9079674; DOI=10.1074/jbc.272.13.8466; RA Valentini R.P., Brookhiser W.T., Park J., Yang T., Briggs J., Dressler G., RA Holzman L.B.; RT "Post-translational processing and renal expression of mouse indian RT hedgehog."; RL J. Biol. Chem. 272:8466-8473(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] OF 76-411. 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 [3] RP SEQUENCE REVISION. RA St Jacques B.; RL Submitted (APR-1997) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 124-172. 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 [5] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=10465785; DOI=10.1101/gad.13.16.2072; RA St-Jacques B., Hammerschmidt M., McMahon A.P.; RT "Indian hedgehog signaling regulates proliferation and differentiation of RT chondrocytes and is essential for bone formation."; RL Genes Dev. 13:2072-2086(1999). RN [6] RP FUNCTION. RX PubMed=10631175; DOI=10.1242/dev.127.3.543; RA Karp S.J., Schipani E., St-Jacques B., Hunzelman J., Kronenberg H., RA McMahon A.P.; RT "Indian hedgehog coordinates endochondral bone growth and morphogenesis via RT parathyroid hormone related-protein-dependent and -independent pathways."; RL Development 127:543-548(2000). RN [7] RP INTERACTION WITH GPC3. RX PubMed=23665349; DOI=10.1016/j.ajpath.2013.03.013; RA Bhave V.S., Mars W., Donthamsetty S., Zhang X., Tan L., Luo J., Bowen W.C., RA Michalopoulos G.K.; RT "Regulation of liver growth by glypican 3, CD81, hedgehog, and Hhex."; RL Am. J. Pathol. 183:153-159(2013). CC -!- FUNCTION: [Indian hedgehog protein]: The C-terminal part of the indian CC hedgehog protein precursor displays an autoproteolysis and a CC cholesterol transferase activity (By similarity). Both activities CC result in the cleavage of the full-length protein into two parts CC followed by the covalent attachment of a cholesterol moiety to the C- CC terminal of the newly generated N-product (By similarity). Both CC activities occur in the reticulum endoplasmic (By similarity). Plays a CC role in hedgehog paracrine signaling. Associated with the very-low- CC density lipoprotein (VLDL) particles to function as a circulating CC morphogen for endothelial cell integrity maintenance (By similarity). CC {ECO:0000250|UniProtKB:Q14623, ECO:0000250|UniProtKB:Q62226}. CC -!- FUNCTION: [Indian hedgehog protein N-product]: The dually lipidated CC indian hedgehog protein N-product is a morphogen which is essential for CC a variety of patterning events during development. Binds to the patched CC (PTCH1) receptor, which functions in association with smoothened (SMO), CC to activate the transcription of target genes (By similarity). Plays a CC role in morphogenesis of the skeleton by coordinating growth and CC differentiation of the endochondral skeleton (PubMed:10465785, CC PubMed:10631175). Positively regulates PTHLH during endochondral bone CC formation preventing chondrocyte hypertrophy. In contrast, Ihh is CC necessary for normal chondrocyte proliferation in a PTHLH-independent CC pathway (PubMed:10631175). {ECO:0000250|UniProtKB:Q15465, CC ECO:0000250|UniProtKB:Q62226, ECO:0000269|PubMed:10465785, CC ECO:0000269|PubMed:10631175}. CC -!- CATALYTIC ACTIVITY: [Indian 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:0000250|UniProtKB:Q62226}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59505; CC Evidence={ECO:0000250|UniProtKB:Q62226}; CC -!- SUBUNIT: [Indian hedgehog protein N-product]: Multimer. CC {ECO:0000250|UniProtKB:Q14623}. CC -!- SUBUNIT: Interacts with BOC and CDON. Interacts with PTCH1 (By CC similarity). Interacts with glypican GPC3 (PubMed:23665349). CC {ECO:0000250|UniProtKB:Q14623, ECO:0000269|PubMed:23665349}. CC -!- SUBCELLULAR LOCATION: [Indian hedgehog protein N-product]: Cell CC membrane {ECO:0000250|UniProtKB:Q14623}; Lipid-anchor CC {ECO:0000250|UniProtKB:Q62226}. Note=The N-product remains associated CC with the cell surface. {ECO:0000250|UniProtKB:Q15465}. CC -!- SUBCELLULAR LOCATION: [Indian hedgehog protein]: Endoplasmic reticulum CC membrane {ECO:0000250|UniProtKB:Q15465}. Golgi apparatus membrane CC {ECO:0000250|UniProtKB:Q15465}. Secreted CC {ECO:0000250|UniProtKB:Q14623}. Note=Co-localizes with HHAT in the ER CC and Golgi membrane. {ECO:0000250|UniProtKB:Q15465}. CC -!- TISSUE SPECIFICITY: In the adult kidney, found in proximal convoluted CC and proximal straight tubule. {ECO:0000269|PubMed:9079674}. CC -!- DEVELOPMENTAL STAGE: Detected at 10 dpc in developing gut, at 14.5 days CC dpc in the cartilage primordium and in the developing urogenital sinus. CC Expression increases with gestional age in kidney and duodenum, CC becoming maximal in adulthood. {ECO:0000269|PubMed:9079674}. CC -!- DOMAIN: [Indian 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:0000250|UniProtKB:Q14623}. CC -!- PTM: [Indian hedgehog protein N-product]: Cholesterylation is required CC for N-product targeting to lipid rafts and multimerization. CC {ECO:0000250|UniProtKB:Q14623}. CC -!- PTM: [Indian hedgehog protein]: The C-terminal domain displays an CC autoproteolysis activity and a cholesterol transferase activity (By CC similarity). Both activities result in the cleavage of the full-length CC protein and covalent attachment of a cholesterol moiety to the C- CC terminal of the newly generated N-product (By similarity). The N- CC product is the active species in both local and long-range signaling, CC whereas the C-product is degraded in the reticulum endoplasmic (By CC similarity). {ECO:0000250|UniProtKB:Q15465, CC ECO:0000250|UniProtKB:Q62226}. CC -!- PTM: [Indian hedgehog protein N-product]: N-palmitoylation by HHAT of CC N-product is required for indian hedgehog protein N-product CC multimerization and full activity. {ECO:0000250|UniProtKB:Q14623}. CC -!- DISRUPTION PHENOTYPE: Almost half of homozygous embryos mice for IHH CC died between 10.5 and 12.5 dpc. Also some lethality occurred in late CC gestation, most of the remaining embryos developed to term but died at CC birth, due to respiratory failure. Mutants display markedly reduced CC chondrocyte proliferation, maturation of chondrocytes at inappropriate CC position, and a failure of osteoblast development in endochondral CC bones. {ECO:0000269|PubMed:10465785}. CC -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB49692.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U85610; AAB49692.1; ALT_INIT; mRNA. DR EMBL; X76291; CAA53923.1; -; mRNA. DR CCDS; CCDS15061.2; -. DR PIR; C49425; C49425. DR RefSeq; NP_034674.2; NM_010544.3. DR AlphaFoldDB; P97812; -. DR SMR; P97812; -. DR BioGRID; 200599; 2. DR DIP; DIP-59800N; -. DR IntAct; P97812; 1. DR STRING; 10090.ENSMUSP00000128056; -. DR MEROPS; C46.003; -. DR GlyCosmos; P97812; 1 site, No reported glycans. DR GlyGen; P97812; 1 site. DR MaxQB; P97812; -. DR PaxDb; 10090-ENSMUSP00000128056; -. DR PeptideAtlas; P97812; -. DR ProteomicsDB; 267304; -. DR Antibodypedia; 3977; 557 antibodies from 37 providers. DR DNASU; 16147; -. DR Ensembl; ENSMUST00000164097.4; ENSMUSP00000128056.3; ENSMUSG00000006538.13. DR GeneID; 16147; -. DR KEGG; mmu:16147; -. DR AGR; MGI:96533; -. DR CTD; 3549; -. DR MGI; MGI:96533; Ihh. DR VEuPathDB; HostDB:ENSMUSG00000006538; -. DR eggNOG; KOG3638; Eukaryota. DR GeneTree; ENSGT00940000159207; -. DR InParanoid; P97812; -. DR OMA; APAVRGC; -. DR OrthoDB; 197397at2759; -. DR PhylomeDB; P97812; -. 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; 16147; 4 hits in 79 CRISPR screens. DR ChiTaRS; Ihh; mouse. DR PRO; PR:P97812; -. DR Proteomes; UP000000589; Chromosome 1. DR RNAct; P97812; Protein. DR Bgee; ENSMUSG00000006538; Expressed in forelimb zeugopod and 145 other cell types or tissues. 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; ISO:MGI. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; ISO:MGI. DR GO; GO:0005509; F:calcium ion binding; ISO:MGI. DR GO; GO:0140853; F:cholesterol-protein transferase activity; ISS:UniProtKB. DR GO; GO:0005113; F:patched binding; IPI:BHF-UCL. DR GO; GO:0008233; F:peptidase activity; ISS:UniProtKB. DR GO; GO:0034189; F:very-low-density lipoprotein particle binding; ISS:UniProtKB. DR GO; GO:0045453; P:bone resorption; IDA:MGI. DR GO; GO:0001569; P:branching involved in blood vessel morphogenesis; IMP:MGI. DR GO; GO:0043010; P:camera-type eye development; IMP:MGI. DR GO; GO:0060220; P:camera-type eye photoreceptor cell fate commitment; IMP:MGI. DR GO; GO:0051216; P:cartilage development; IMP:MGI. DR GO; GO:0001708; P:cell fate specification; IMP:MGI. DR GO; GO:0048469; P:cell maturation; IMP:MGI. DR GO; GO:0008283; P:cell population proliferation; IMP:MGI. DR GO; GO:0007267; P:cell-cell signaling; IEA:InterPro. DR GO; GO:0002062; P:chondrocyte differentiation; IDA:MGI. DR GO; GO:0003413; P:chondrocyte differentiation involved in endochondral bone morphogenesis; IMP:MGI. DR GO; GO:0035988; P:chondrocyte proliferation; IMP:MGI. DR GO; GO:0048596; P:embryonic camera-type eye morphogenesis; IMP:MGI. DR GO; GO:0048557; P:embryonic digestive tract morphogenesis; IMP:MGI. DR GO; GO:0042733; P:embryonic digit morphogenesis; IMP:MGI. DR GO; GO:0009880; P:embryonic pattern specification; IMP:MGI. DR GO; GO:0072498; P:embryonic skeletal joint development; IMP:MGI. DR GO; GO:0003382; P:epithelial cell morphogenesis; IMP:MGI. DR GO; GO:0090136; P:epithelial cell-cell adhesion; IMP:MGI. DR GO; GO:0060323; P:head morphogenesis; IMP:MGI. DR GO; GO:0001947; P:heart looping; IMP:BHF-UCL. DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI. DR GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro. DR GO; GO:0097421; P:liver regeneration; IEA:Ensembl. DR GO; GO:0060135; P:maternal process involved in female pregnancy; IEA:Ensembl. DR GO; GO:0001763; P:morphogenesis of a branching structure; IMP:MGI. DR GO; GO:0035264; P:multicellular organism growth; IMP:MGI. DR GO; GO:0046639; P:negative regulation of alpha-beta T cell differentiation; IMP:BHF-UCL. DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:MGI. DR GO; GO:0032331; P:negative regulation of chondrocyte differentiation; IMP:MGI. DR GO; GO:0048074; P:negative regulation of eye pigmentation; IMP:MGI. DR GO; GO:0033088; P:negative regulation of immature T cell proliferation in thymus; IMP:BHF-UCL. DR GO; GO:0033085; P:negative regulation of T cell differentiation in thymus; IMP:BHF-UCL. DR GO; GO:0048666; P:neuron development; IMP:MGI. DR GO; GO:0001503; P:ossification; IMP:MGI. DR GO; GO:0001649; P:osteoblast differentiation; IDA:MGI. DR GO; GO:0031016; P:pancreas development; IMP:MGI. DR GO; GO:0007389; P:pattern specification process; IMP:MGI. DR GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; IMP:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:MGI. DR GO; GO:0032967; P:positive regulation of collagen biosynthetic process; IDA:MGI. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISO:MGI. DR GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; IMP:MGI. DR GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IMP:BHF-UCL. 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; IGI:MGI. DR GO; GO:0016540; P:protein autoprocessing; IEA:InterPro. DR GO; GO:0006029; P:proteoglycan metabolic process; IGI:MGI. DR GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central. DR GO; GO:0040008; P:regulation of growth; IGI:MGI. DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl. DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl. DR GO; GO:0003406; P:retinal pigment epithelium development; IMP:MGI. DR GO; GO:0097264; P:self proteolysis; ISS:UniProtKB. DR GO; GO:0001501; P:skeletal system development; IMP:MGI. DR GO; GO:0048745; P:smooth muscle tissue development; IMP:MGI. DR GO; GO:0007224; P:smoothened signaling pathway; IDA:MGI. DR GO; GO:0061053; P:somite development; IMP:BHF-UCL. DR GO; GO:0001944; P:vasculature development; IMP:MGI. DR GO; GO:0030704; P:vitelline membrane formation; IMP:MGI. DR CDD; cd00081; Hint; 1. DR Gene3D; 3.30.1380.10; -; 1. DR Gene3D; 2.170.16.10; Hedgehog/Intein (Hint) domain; 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 PANTHER; PTHR11889; HEDGEHOG; 1. DR PANTHER; PTHR11889:SF39; INDIAN HEDGEHOG PROTEIN; 1. 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; SSF55166; Hedgehog/DD-peptidase; 1. DR SUPFAM; SSF51294; Hedgehog/intein (Hint) domain; 1. DR PROSITE; PS50817; INTEIN_N_TER; 1. PE 1: Evidence at protein level; KW Autocatalytic cleavage; Calcium; Cell membrane; Developmental protein; KW Endoplasmic reticulum; Glycoprotein; Golgi apparatus; Hydrolase; KW Lipoprotein; Membrane; Metal-binding; Palmitate; Protease; KW Reference proteome; Secreted; Signal; Transferase; Zinc. FT SIGNAL 1..27 FT /evidence="ECO:0000255" FT CHAIN 28..411 FT /note="Indian hedgehog protein" FT /id="PRO_0000013232" FT CHAIN 28..202 FT /note="Indian hedgehog protein N-product" FT /id="PRO_0000013233" FT BINDING 94 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 95 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 95 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 100 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 130 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 131 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 131 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 134 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 136 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 145 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 152 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT BINDING 187 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT SITE 202..203 FT /note="Cleavage; by autolysis" FT SITE 248 FT /note="Involved in cholesterol transfer" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT SITE 272 FT /note="Involved in auto-cleavage" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT SITE 275 FT /note="Essential for auto-cleavage" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT LIPID 28 FT /note="N-palmitoyl cysteine" FT /evidence="ECO:0000250|UniProtKB:Q14623" FT LIPID 202 FT /note="Cholesterol glycine ester" FT /evidence="ECO:0000250|UniProtKB:Q02936" FT CARBOHYD 282 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CONFLICT 383 FT /note="W -> S (in Ref. 2)" FT /evidence="ECO:0000305" SQ SEQUENCE 411 AA; 45485 MW; 08BE7AD8507C0D9B CRC64; MSPAWLRPRL RFCLFLLLLL LVPAARGCGP GRVVGSRRRP PRKLVPLAYK QFSPNVPEKT LGASGRYEGK IARSSERFKE LTPNYNPDII FKDEENTGAD RLMTQRCKDR LNSLAISVMN QWPGVKLRVT EGWDEDGHHS EESLHYEGRA VDITTSDRDR NKYGLLARLA VEAGFDWVYY ESKAHVHCSV KSEHSAAAKT GGCFPAGAQV RLENGERVAL SAVKPGDRVL AMGEDGTPTF SDVLIFLDRE PNRLRAFQVI ETQDPPRRLA LTPAHLLFIA DNHTEPAAHF RATFASHVQP GQYVLVSGVP GLQPARVAAV STHVALGSYA PLTRHGTLVV EDVVASCFAA VADHHLAQLA FWPLRLFPSL AWGSWTPSEG VHWYPQMLYR LGRLLLEEST FHPLGMSGAG S //