IHH_MOUSE
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 03-AUG-2022, entry version 190.
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 DIP; DIP-59800N; -.
DR IntAct; P97812; 1.
DR STRING; 10090.ENSMUSP00000128056; -.
DR MEROPS; C46.003; -.
DR GlyGen; P97812; 1 site.
DR MaxQB; P97812; -.
DR PaxDb; P97812; -.
DR PeptideAtlas; P97812; -.
DR PRIDE; P97812; -.
DR ProteomicsDB; 267304; -.
DR Antibodypedia; 3977; 529 antibodies from 37 providers.
DR DNASU; 16147; -.
DR Ensembl; ENSMUST00000164097; ENSMUSP00000128056; ENSMUSG00000006538.
DR GeneID; 16147; -.
DR KEGG; mmu:16147; -.
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; 1169356at2759; -.
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; 3 hits in 74 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 141 other tissues.
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; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0005509; F:calcium ion binding; ISO:MGI.
DR GO; GO:0005113; F:patched binding; IPI:BHF-UCL.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
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: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 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; IPR033385; IHH.
DR InterPro; IPR006141; Intein_N.
DR PANTHER; PTHR11889:SF39; PTHR11889:SF39; 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; SSF51294; SSF51294; 1.
DR SUPFAM; SSF55166; SSF55166; 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; 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
