INVS_MOUSE
ID INVS_MOUSE Reviewed; 1062 AA.
AC O89019; O88849;
DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 2.
DT 25-MAY-2022, entry version 153.
DE RecName: Full=Inversin;
DE AltName: Full=Inversion of embryo turning protein;
DE AltName: Full=Nephrocystin-2;
GN Name=Invs; Synonyms=Inv, Nphp2;
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], FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL
RP STAGE, AND DISRUPTION PHENOTYPE.
RC TISSUE=Embryo;
RX PubMed=9744276; DOI=10.1038/26006;
RA Mochizuki T., Saijoh Y., Tsuchiya K., Shirayoshi Y., Takai S., Taya C.,
RA Yonekawa H., Yamada K., Nihei H., Nakatsuji N., Overbeek P.A., Hamada H.,
RA Yokoyama T.;
RT "Cloning of inv, a gene that controls left/right asymmetry and kidney
RT development.";
RL Nature 395:177-181(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), NUCLEOTIDE SEQUENCE
RP [GENOMIC DNA] OF 92-1062, AND FUNCTION.
RC STRAIN=FVB/N; TISSUE=Embryo;
RX PubMed=9771707; DOI=10.1038/2450;
RA Morgan D., Turnpenny L., Goodship J., Dai W., Majumder K., Matthews L.,
RA Gardner A., Schuster G., Vien L., Harrison W., Elder F.F.B.,
RA Penman-Splitt M., Overbeek P., Strachan T.;
RT "Inversin, a novel gene in the vertebrate left-right axis pathway, is
RT partially deleted in the inv mouse.";
RL Nat. Genet. 20:149-156(1998).
RN [3]
RP ALTERNATIVE SPLICING (ISOFORMS 1; 2; 3; 4; 5; 6 AND 7).
RX PubMed=15533716; DOI=10.1016/j.ygeno.2004.08.002;
RA Ward H.H., Wang J., Phillips C.;
RT "Analysis of multiple Invs transcripts in mouse and MDCK cells.";
RL Genomics 84:991-1001(2004).
RN [4]
RP SUBCELLULAR LOCATION.
RX PubMed=12642479; DOI=10.1242/dev.00407;
RA Watanabe D., Saijoh Y., Nonaka S., Sasaki G., Ikawa Y., Yokoyama T.,
RA Hamada H.;
RT "The left-right determinant Inversin is a component of node monocilia and
RT other 9+0 cilia.";
RL Development 130:1725-1734(2003).
RN [5]
RP CALMODULIN-BINDING.
RX PubMed=11941489; DOI=10.1007/s00439-002-0696-4;
RA Morgan D., Goodship J., Essner J.J., Vogan K.J., Turnpenny L., Yost H.J.,
RA Tabin C.J., Strachan T.;
RT "The left-right determinant inversin has highly conserved ankyrin repeat
RT and IQ domains and interacts with calmodulin.";
RL Hum. Genet. 110:377-384(2002).
RN [6]
RP TISSUE SPECIFICITY, INTERACTION WITH APC2, AND MUTAGENESIS OF ASN-498 AND
RP ASN-915.
RX PubMed=12471060; DOI=10.1093/hmg/11.26.3345;
RA Morgan D., Eley L., Sayer J., Strachan T., Yates L.M., Craighead A.S.,
RA Goodship J.A.;
RT "Expression analyses and interaction with the anaphase promoting complex
RT protein Apc2 suggest a role for inversin in primary cilia and involvement
RT in the cell cycle.";
RL Hum. Mol. Genet. 11:3345-3350(2002).
RN [7]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH CATENINS AND CDH2.
RX PubMed=12221118; DOI=10.1091/mbc.e02-04-0195;
RA Nuernberger J., Bacallao R.L., Phillips C.L.;
RT "Inversin forms a complex with catenins and N-cadherin in polarized
RT epithelial cells.";
RL Mol. Biol. Cell 13:3096-3106(2002).
RN [8]
RP FUNCTION.
RX PubMed=21565611; DOI=10.1016/j.cell.2011.04.019;
RA Sang L., Miller J.J., Corbit K.C., Giles R.H., Brauer M.J., Otto E.A.,
RA Baye L.M., Wen X., Scales S.J., Kwong M., Huntzicker E.G., Sfakianos M.K.,
RA Sandoval W., Bazan J.F., Kulkarni P., Garcia-Gonzalo F.R., Seol A.D.,
RA O'Toole J.F., Held S., Reutter H.M., Lane W.S., Rafiq M.A., Noor A.,
RA Ansar M., Devi A.R., Sheffield V.C., Slusarski D.C., Vincent J.B.,
RA Doherty D.A., Hildebrandt F., Reiter J.F., Jackson P.K.;
RT "Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes
RT and pathways.";
RL Cell 145:513-528(2011).
CC -!- FUNCTION: Required for normal renal development and establishment of
CC left-right axis. Probably acts as a molecular switch between different
CC Wnt signaling pathways. Inhibits the canonical Wnt pathway by targeting
CC cytoplasmic disheveled (DVL1) for degradation by the ubiquitin-
CC proteasome. This suggests that it is required in renal development to
CC oppose the repression of terminal differentiation of tubular epithelial
CC cells by Wnt signaling (By similarity). Involved in the organization of
CC apical junctions in kidney cells together with NPHP1, NPHP4 and
CC RPGRIP1L/NPHP8. Does not seem to be strictly required for ciliogenesis.
CC {ECO:0000250, ECO:0000269|PubMed:21565611, ECO:0000269|PubMed:9744276,
CC ECO:0000269|PubMed:9771707}.
CC -!- SUBUNIT: Interacts with microtubules. Interacts with NPHP1. Interacts
CC with DVL1, PRICKLE (PRICKLE1 or PRICKLE2) and Strabismus (VANGL1 or
CC VANGL2) (By similarity). Binds calmodulin via its IQ domains. Interacts
CC with APC2. Interacts with alpha-, beta-, and gamma-catenin. Interacts
CC with N-cadherin (CDH2). Interacts with NPHP3 (By similarity). Interacts
CC with IQCB1; the interaction likely requires additional interactors (By
CC similarity). Component of a complex containing at least ANKS6, INVS,
CC NEK8 and NPHP3. ANKS6 may organize complex assembly by linking INVS and
CC NPHP3 to NEK8 and INVS may target the complex to the proximal ciliary
CC axoneme (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC O89019; Q8BP00: Iqcb1; NbExp=2; IntAct=EBI-4281337, EBI-4282243;
CC O89019; Q91ZR4: Nek8; NbExp=2; IntAct=EBI-4281337, EBI-4282339;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, cytoskeleton. Membrane;
CC Peripheral membrane protein. Nucleus. Cytoplasm, perinuclear region.
CC Cytoplasm, cytoskeleton, spindle. Note=Associates with several
CC components of the cytoskeleton including ciliary, random and polarized
CC microtubules. During mitosis, it is recruited to mitotic spindle (By
CC similarity). Membrane localization is dependent upon cell-cell contacts
CC and is redistributed when cell adhesion is disrupted after incubation
CC of the cell monolayer with low-calcium/EGTA medium. Also nuclear and
CC perinuclear. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=1; Synonyms=F;
CC IsoId=O89019-1; Sequence=Displayed;
CC Name=2; Synonyms=S2;
CC IsoId=O89019-2; Sequence=VSP_014505;
CC Name=3; Synonyms=S1;
CC IsoId=O89019-3; Sequence=VSP_014506;
CC Name=4;
CC IsoId=O89019-4; Sequence=VSP_014498;
CC Name=5;
CC IsoId=O89019-5; Sequence=VSP_014499, VSP_014500;
CC Name=6;
CC IsoId=O89019-6; Sequence=VSP_014503, VSP_014504;
CC Name=7;
CC IsoId=O89019-7; Sequence=VSP_014501, VSP_014502;
CC -!- TISSUE SPECIFICITY: Strongly expressed in the primary cilia of renal
CC cells, especially in the varicosities, swellings observed in the cilia.
CC Localizes in the node monocilia and in other 9+0 monocilia, including
CC those of kidney epithelial cells and the pituitary gland, but it does
CC not localize to 9+2 cilia (at protein level). In adult, it is expressed
CC at high level in liver and kidney. Weakly or not expressed in other
CC tissues. {ECO:0000269|PubMed:12471060, ECO:0000269|PubMed:9744276}.
CC -!- DEVELOPMENTAL STAGE: Expressed from 7 dpc. Expressed in presomite-stage
CC embryos, before asymmetrical expression of Nodal and Lefty.
CC {ECO:0000269|PubMed:9744276}.
CC -!- DOMAIN: The D-box 1 (destruction box 1) mediates the interaction with
CC APC2, and may act as a recognition signal for degradation via the
CC ubiquitin-proteasome pathway.
CC -!- PTM: May be ubiquitinated via its interaction with APC2.
CC -!- PTM: Hydroxylated at Asn-75, most probably by HIF1AN. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Constant reversal of left/right polarity (situs
CC inversus) and cyst formation in the kidneys.
CC {ECO:0000269|PubMed:9744276}.
CC -!- MISCELLANEOUS: [Isoform 2]: Exon 14b skipped. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Exon 14a skipped. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 4]: Exon 5 skipped. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 5]: Exon 13 skipped. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 7]: Exon 13 skipped with exon 14b.
CC {ECO:0000305}.
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DR EMBL; AF034860; AAC34976.3; -; mRNA.
DR EMBL; AJ004828; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AJ010902; CAA09388.1; -; mRNA.
DR CCDS; CCDS18166.1; -. [O89019-1]
DR PIR; T14151; T14151.
DR PIR; T30255; T30255.
DR AlphaFoldDB; O89019; -.
DR SMR; O89019; -.
DR IntAct; O89019; 7.
DR MINT; O89019; -.
DR STRING; 10090.ENSMUSP00000030029; -.
DR iPTMnet; O89019; -.
DR PhosphoSitePlus; O89019; -.
DR PaxDb; O89019; -.
DR PRIDE; O89019; -.
DR ProteomicsDB; 268976; -. [O89019-1]
DR ProteomicsDB; 268977; -. [O89019-2]
DR ProteomicsDB; 268978; -. [O89019-3]
DR ProteomicsDB; 268979; -. [O89019-4]
DR ProteomicsDB; 268980; -. [O89019-5]
DR ProteomicsDB; 268981; -. [O89019-6]
DR ProteomicsDB; 268982; -. [O89019-7]
DR MGI; MGI:1335082; Invs.
DR eggNOG; KOG0504; Eukaryota.
DR InParanoid; O89019; -.
DR PhylomeDB; O89019; -.
DR ChiTaRS; Invs; mouse.
DR PRO; PR:O89019; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; O89019; protein.
DR GO; GO:0097546; C:ciliary base; IDA:MGI.
DR GO; GO:0097543; C:ciliary inversin compartment; IDA:MGI.
DR GO; GO:0005576; C:extracellular region; IEA:GOC.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005819; C:spindle; IEA:UniProtKB-SubCell.
DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW.
DR GO; GO:0048513; P:animal organ development; IMP:MGI.
DR GO; GO:0060971; P:embryonic heart tube left/right pattern formation; IMP:MGI.
DR GO; GO:0060287; P:epithelial cilium movement involved in determination of left/right asymmetry; IMP:MGI.
DR GO; GO:0001822; P:kidney development; IMP:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0031016; P:pancreas development; IMP:MGI.
DR GO; GO:0009791; P:post-embryonic development; IMP:MGI.
DR GO; GO:1904108; P:protein localization to ciliary inversin compartment; IMP:MGI.
DR GO; GO:0006468; P:protein phosphorylation; IMP:MGI.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR Gene3D; 1.25.40.20; -; 4.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR InterPro; IPR000048; IQ_motif_EF-hand-BS.
DR Pfam; PF00023; Ank; 3.
DR Pfam; PF12796; Ank_2; 4.
DR Pfam; PF00612; IQ; 2.
DR SMART; SM00248; ANK; 15.
DR SMART; SM00015; IQ; 2.
DR SUPFAM; SSF48403; SSF48403; 2.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 11.
DR PROSITE; PS50096; IQ; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; ANK repeat; Calmodulin-binding; Cytoplasm;
KW Cytoskeleton; Developmental protein; Hydroxylation; Membrane; Microtubule;
KW Nucleus; Reference proteome; Repeat; Ubl conjugation;
KW Wnt signaling pathway.
FT CHAIN 1..1062
FT /note="Inversin"
FT /id="PRO_0000067017"
FT REPEAT 13..42
FT /note="ANK 1"
FT REPEAT 47..76
FT /note="ANK 2"
FT REPEAT 80..110
FT /note="ANK 3"
FT REPEAT 113..144
FT /note="ANK 4"
FT REPEAT 148..177
FT /note="ANK 5"
FT REPEAT 181..213
FT /note="ANK 6"
FT REPEAT 220..250
FT /note="ANK 7"
FT REPEAT 254..283
FT /note="ANK 8"
FT REPEAT 288..317
FT /note="ANK 9"
FT REPEAT 321..350
FT /note="ANK 10"
FT REPEAT 356..385
FT /note="ANK 11"
FT REPEAT 389..418
FT /note="ANK 12"
FT REPEAT 422..451
FT /note="ANK 13"
FT REPEAT 455..484
FT /note="ANK 14"
FT REPEAT 488..517
FT /note="ANK 15"
FT REPEAT 523..553
FT /note="ANK 16"
FT DOMAIN 555..584
FT /note="IQ 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00116"
FT DOMAIN 914..943
FT /note="IQ 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00116"
FT REGION 589..849
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1042..1062
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 490..498
FT /note="D-box 1"
FT MOTIF 907..915
FT /note="D-box 2"
FT COMPBIAS 589..614
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 635..660
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 677..691
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 724..743
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 776..804
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 75
FT /note="3-hydroxyasparagine"
FT /evidence="ECO:0000250"
FT VAR_SEQ 150..205
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_014498"
FT VAR_SEQ 489..492
FT /note="GRTA -> VHTP (in isoform 5)"
FT /evidence="ECO:0000305"
FT /id="VSP_014499"
FT VAR_SEQ 493..1062
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000305"
FT /id="VSP_014500"
FT VAR_SEQ 596..755
FT /note="KREEENKRKEAEQQKGQLDTDPPRSHCSSSAPVLPCPPSPQNEGSKQDATPS
FT KQPPASHTVQSPDPEHSRLPGRCPGRASQGDSSIDLQGTASRKPSETPIEHCRGPSACV
FT HPRSWEGGNSSKNQGTSSVEKRRGETNGKHRRCEEGPSSARQPLCTGSG -> NTHRAL
FT QRPFCLCAPQILGRWQQLQEPGNILCGEAQRAAPADNPEGTKQERAVSTEKQGSGGHPA
FT SLAKLPAQEAPVSASAFEAAWSQRSAQMYPSVHSPAPPGLEERTGTQIPKVHLSKQDIE
FT ESIQRLVGHKVCQALSAQADLRLFSRRERTSSHQIF (in isoform 7)"
FT /evidence="ECO:0000305"
FT /id="VSP_014501"
FT VAR_SEQ 596..632
FT /note="KREEENKRKEAEQQKGQLDTDPPRSHCSSSAPVLPCP -> NTHRALQRPFC
FT LCAPQILGRWQQLQEPGNILCGEAQR (in isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_014503"
FT VAR_SEQ 633..1062
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_014504"
FT VAR_SEQ 730..894
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9771707"
FT /id="VSP_014505"
FT VAR_SEQ 730..849
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:9771707"
FT /id="VSP_014506"
FT VAR_SEQ 756..1062
FT /note="Missing (in isoform 7)"
FT /evidence="ECO:0000305"
FT /id="VSP_014502"
FT MUTAGEN 498
FT /note="N->A: Abolishes interaction with APC2."
FT /evidence="ECO:0000269|PubMed:12471060"
FT MUTAGEN 915
FT /note="N->A: Does not affect interaction with APC2."
FT /evidence="ECO:0000269|PubMed:12471060"
FT CONFLICT 23
FT /note="V -> I (in Ref. 2; CAA09388)"
FT /evidence="ECO:0000305"
FT CONFLICT 32
FT /note="R -> K (in Ref. 2; CAA09388)"
FT /evidence="ECO:0000305"
FT CONFLICT 320
FT /note="L -> Q (in Ref. 2; CAA09388)"
FT /evidence="ECO:0000305"
FT CONFLICT 460..462
FT /note="LQC -> IQS (in Ref. 2; CAA09388)"
FT /evidence="ECO:0000305"
FT CONFLICT 468
FT /note="Y -> N (in Ref. 2; CAA09388)"
FT /evidence="ECO:0000305"
FT CONFLICT 639
FT /note="G -> A (in Ref. 2; CAA09388)"
FT /evidence="ECO:0000305"
FT CONFLICT 666
FT /note="L -> P (in Ref. 2; CAA09388)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1062 AA; 117129 MW; 048DF1D94F23C033 CRC64;
MNISEDVLST GSSLASQVHA AAVNGDKGAL QRLIVGNSAL RDKEDRFGRT PLMYCVLADR
VDCADALLKA GADVNKTDHS RRTALHLAAQ KGNYRFMKLL LTRRANWMQK DLEEMTPLHL
STRHRSPKCL ALLLKFMAPG EVDTQDKNKQ TALHWSAYYN NPEHAKLLIK HDSNIGIPDV
EGKIPLHWAA NHKDPSAVHT VRCILDAAPT ESLLNWQDYE GRTPLHFAVA DGNLTVVDVL
TSYESCNITS YDNLFRTPLH WAALLGHAQI VHLLLERNKS GTIPSDSQGA TPLHYAAQSN
FAETVKVFLQ HPSVKDDSDL EGRTSFMWAA GKGNDDVLRT MLSLKSDIDI NMSDKYGGTA
LHAAALSGHV STVKLLLDND AQVDATDVMK HTPLFRACEM GHRDVIQTLI KGGARVDLVD
QDGHSLLHWA ALGGNADVCQ ILIENKINPN VQDYAGRTPL QCAAYGGYIN CMAVLMENNA
DPNIQDKEGR TALHWSCNNG YLDAIKLLLD FAAFPNQMEN NEERYTPLDY ALLGERHEVI
QFMLEHGALS IAAIQDIAAF KIQAVYKGYK VRKAFRDRKN LLMKHEQLRK DAAAKKREEE
NKRKEAEQQK GQLDTDPPRS HCSSSAPVLP CPPSPQNEGS KQDATPSKQP PASHTVQSPD
PEHSRLPGRC PGRASQGDSS IDLQGTASRK PSETPIEHCR GPSACVHPRS WEGGNSSKNQ
GTSSVEKRRG ETNGKHRRCE EGPSSARQPL CTGSGRPAEK GEDSSPAVAS ASQQDHPRKP
NKRQDRAARP RGASQKRRTH QLRDRCSPAG SSRPGSAKGE VACADQSSLH RHTPRSKVTQ
DKLIGGVSSG LPLSTEASRS GCKQLYEDIC ASPETGVAHG PPPGQCMNIH LLPVEQRLLI
IQRERSRKEL FRRKNKAAAV IQRAWRSYQL RKHLSRLLHL KQLGAREVLR CTQVCTALLL
QVWRKELELK FPKSISVSRT SKSPSKGSSA TKYARHSVLR QIYGCSQEGK GHHPIKSSKA
PAVLHLSSVN SLQSIHLDNS GRSKKFSYNL QPSSQSKNKP KL
