INSM1_HUMAN
ID INSM1_HUMAN Reviewed; 510 AA.
AC Q01101;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=Insulinoma-associated protein 1;
DE AltName: Full=Zinc finger protein IA-1;
GN Name=INSM1; Synonyms=IA1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RX PubMed=1634555; DOI=10.1016/s0021-9258(18)42173-4;
RA Goto Y., de Silva M.G., Toscani A., Prabhakar B.S., Notkins A.L., Lan M.S.;
RT "A novel human insulinoma-associated cDNA, IA-1, encodes a protein with
RT 'zinc-finger' DNA-binding motifs.";
RL J. Biol. Chem. 267:15252-15257(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-11.
RX PubMed=8188699; DOI=10.1016/s0021-9258(17)36770-4;
RA Lan M.S., Li Q., Lu J., Modi W.S., Notkins A.L.;
RT "Genomic organization, 5'-upstream sequence, and chromosomal localization
RT of an insulinoma-associated intronless gene, IA-1.";
RL J. Biol. Chem. 269:14170-14174(1994).
RN [4]
RP FUNCTION, AND DNA-BINDING.
RX PubMed=11842116; DOI=10.1093/nar/30.4.1038;
RA Breslin M.B., Zhu M., Notkins A.L., Lan M.S.;
RT "Neuroendocrine differentiation factor, IA-1, is a transcriptional
RT repressor and contains a specific DNA-binding domain: identification of
RT consensus IA-1 binding sequence.";
RL Nucleic Acids Res. 30:1038-1045(2002).
RN [5]
RP INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=12890672; DOI=10.1074/jbc.m306795200;
RA Breslin M.B., Zhu M., Lan M.S.;
RT "NeuroD1/E47 regulates the E-box element of a novel zinc finger
RT transcription factor, IA-1, in developing nervous system.";
RL J. Biol. Chem. 278:38991-38997(2003).
RN [6]
RP FUNCTION, DNA-BINDING, AND INTERACTION WITH CCND1; HDAC1 AND HDAC3.
RX PubMed=16569215; DOI=10.1042/bj20051669;
RA Liu W.D., Wang H.W., Muguira M., Breslin M.B., Lan M.S.;
RT "INSM1 functions as a transcriptional repressor of the neuroD/beta2 gene
RT through the recruitment of cyclin D1 and histone deacetylases.";
RL Biochem. J. 397:169-177(2006).
RN [7]
RP FUNCTION, AND INDUCTION.
RX PubMed=16511571; DOI=10.1038/sj.emboj.7601011;
RA Mellitzer G., Bonne S., Luco R.F., Van De Casteele M., Lenne-Samuel N.,
RA Collombat P., Mansouri A., Lee J., Lan M., Pipeleers D., Nielsen F.C.,
RA Ferrer J., Gradwohl G., Heimberg H.;
RT "IA1 is NGN3-dependent and essential for differentiation of the endocrine
RT pancreas.";
RL EMBO J. 25:1344-1352(2006).
RN [8]
RP FUNCTION, DNA-BINDING, AND INTERACTION WITH CCND1 AND HDAC3.
RX PubMed=18417529; DOI=10.1677/joe-08-0001;
RA Wang H.W., Muguira M., Liu W.D., Zhang T., Chen C., Aucoin R.,
RA Breslin M.B., Lan M.S.;
RT "Identification of an INSM1-binding site in the insulin promoter: negative
RT regulation of the insulin gene transcription.";
RL J. Endocrinol. 198:29-39(2008).
RN [9]
RP FUNCTION, DNA-BINDING, INTERACTION WITH CCND1, AND MUTAGENESIS OF
RP 43-PRO--PRO-58.
RX PubMed=19124461; DOI=10.1074/jbc.m808843200;
RA Zhang T., Liu W.D., Saunee N.A., Breslin M.B., Lan M.S.;
RT "Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4
RT binding and induces cell cycle arrest.";
RL J. Biol. Chem. 284:5574-5581(2009).
RN [10]
RP REVIEW.
RX PubMed=19246490; DOI=10.1096/fj.08-125971;
RA Lan M.S., Breslin M.B.;
RT "Structure, expression, and biological function of INSM1 transcription
RT factor in neuroendocrine differentiation.";
RL FASEB J. 23:2024-2033(2009).
RN [11]
RP STRUCTURE BY NMR OF 424-497 IN COMPLEX WITH ZINC IONS.
RG Northeast structural genomics consortium (NESG);
RT "Solution NMR structure of C2H2-type zinc-fingers 4 and 5 from human
RT insulinoma-associated protein 1 (fragment 424-497), Northeast structural
RT genomics consortium target HR7614B (Casp target).";
RL Submitted (OCT-2012) to the PDB data bank.
RN [12] {ECO:0007744|PDB:3ZMS}
RP X-RAY CRYSTALLOGRAPHY (2.96 ANGSTROMS) OF 2-9 IN COMPLEX WITH KDM1A,
RP FUNCTION, AND INTERACTION WITH KDM1A.
RX PubMed=23721412; DOI=10.1021/cb4001926;
RA Tortorici M., Borrello M.T., Tardugno M., Chiarelli L.R., Pilotto S.,
RA Ciossani G., Vellore N.A., Bailey S.G., Cowan J., O'Connell M., Crabb S.J.,
RA Packham G., Mai A., Baron R., Ganesan A., Mattevi A.;
RT "Protein recognition by short peptide reversible inhibitors of the
RT chromatin-modifying LSD1/CoREST lysine demethylase.";
RL ACS Chem. Biol. 8:1677-1682(2013).
CC -!- FUNCTION: Sequence-specific DNA-binding transcriptional regulator that
CC plays a key role in neurogenesis and neuroendocrine cell
CC differentiation during embryonic and/or fetal development. Binds to the
CC consensus sequence 5'-[TG][TC][TC][TT][GA]GGG[CG]A-3' in target
CC promoters. Acts as a transcriptional repressor of NEUROD1 and INS
CC expression via its interaction with cyclin CCND1 in a cell cycle-
CC independent manner. Negatively regulates skeletal muscle-specific gene
CC expression in endocrine cells of the pituitary by inhibiting the Notch
CC signaling pathway. Represses target gene transcription by recruiting
CC chromatin-modifying factors, such as HDAC1, HDAC2, HDAC3, KDM1A and
CC RCOR1 histone deacetylases. Binds to its own promoter, suggesting
CC autoregulation as a self-control feedback mechanism. Competes with
CC histone H3 for the same binding site on the histone demethylase complex
CC formed by KDM1A and RCOR1, and thereby inhibits demethylation of
CC histone H3 at 'Lys-4' (PubMed:23721412). Promotes the generation and
CC expansion of neuronal basal progenitor cells in the developing
CC neocortex. Involved in the differentiation of endocrine cells of the
CC developing anterior pituitary gland, of the pancreas and intestine, and
CC of sympatho-adrenal cells in the peripheral nervous system. Promotes
CC cell cycle signaling arrest and inhibition of cellular proliferation.
CC {ECO:0000269|PubMed:11842116, ECO:0000269|PubMed:16511571,
CC ECO:0000269|PubMed:16569215, ECO:0000269|PubMed:18417529,
CC ECO:0000269|PubMed:19124461, ECO:0000269|PubMed:23721412}.
CC -!- SUBUNIT: Interacts (via the SNAG domain) with HDAC1 (PubMed:16569215).
CC Interacts (via the SNAG domain) with HDAC2 (By similarity). Interacts
CC (via the SNAG domain) with KDM1A (PubMed:23721412). Interacts (via the
CC SNAG domain) with RCOR1. Interacts with SORBS1 (By similarity).
CC Interacts (via the N-terminal region) with CCND1 (via cyclin N-terminal
CC domain); the interaction competes with the binding of CCND1 to CDK4
CC during cell cycle progression and increases its transcriptional
CC repressor activity (PubMed:16569215, PubMed:18417529, PubMed:19124461).
CC Interacts with HDAC3; the interaction increases its transcriptional
CC repressor activity (PubMed:16569215, PubMed:18417529).
CC {ECO:0000250|UniProtKB:Q63ZV0, ECO:0000269|PubMed:16569215,
CC ECO:0000269|PubMed:18417529, ECO:0000269|PubMed:19124461,
CC ECO:0000269|PubMed:23721412}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q63ZV0}.
CC -!- TISSUE SPECIFICITY: Expressed in pancreatic duct cells. Expressed in
CC several tumor cell lines of neuroendocrine origin including
CC pheochromocytoma, medullary thyroid carcinoma, insulinoma,
CC medulloblastoma, retinoblastoma, pheochromacytoma, medullary thyroid
CC carcinoma and small cell lung carcinoma. {ECO:0000269|PubMed:12890672,
CC ECO:0000269|PubMed:1634555}.
CC -!- INDUCTION: Up-regulated by transcription factors, such as MASH1,
CC NEUROD1, NEUROG3, NGN3 and TCF3. {ECO:0000269|PubMed:12890672,
CC ECO:0000269|PubMed:16511571}.
CC -!- DOMAIN: The C-terminal region is necessary for NEUROD1 promoter DNA-
CC binding and transcriptional repressor activity.
CC -!- SIMILARITY: Belongs to the INSM1 family. {ECO:0000305}.
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DR EMBL; M93119; AAA58680.1; -; mRNA.
DR EMBL; AL161658; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; U07172; AAA20938.1; -; Genomic_DNA.
DR CCDS; CCDS13143.1; -.
DR PIR; A42750; A42750.
DR RefSeq; NP_002187.1; NM_002196.2.
DR PDB; 2LV2; NMR; -; A=424-497.
DR PDB; 3ZMS; X-ray; 2.96 A; C=2-9.
DR PDBsum; 2LV2; -.
DR PDBsum; 3ZMS; -.
DR AlphaFoldDB; Q01101; -.
DR BMRB; Q01101; -.
DR SMR; Q01101; -.
DR BioGRID; 109853; 7.
DR IntAct; Q01101; 5.
DR STRING; 9606.ENSP00000312631; -.
DR iPTMnet; Q01101; -.
DR PhosphoSitePlus; Q01101; -.
DR BioMuta; INSM1; -.
DR DMDM; 547700; -.
DR EPD; Q01101; -.
DR jPOST; Q01101; -.
DR MassIVE; Q01101; -.
DR PaxDb; Q01101; -.
DR PeptideAtlas; Q01101; -.
DR PRIDE; Q01101; -.
DR ProteomicsDB; 57916; -.
DR Antibodypedia; 9637; 85 antibodies from 24 providers.
DR DNASU; 3642; -.
DR Ensembl; ENST00000310227.3; ENSP00000312631.1; ENSG00000173404.5.
DR GeneID; 3642; -.
DR KEGG; hsa:3642; -.
DR MANE-Select; ENST00000310227.3; ENSP00000312631.1; NM_002196.3; NP_002187.1.
DR UCSC; uc002wrx.4; human.
DR CTD; 3642; -.
DR DisGeNET; 3642; -.
DR GeneCards; INSM1; -.
DR HGNC; HGNC:6090; INSM1.
DR HPA; ENSG00000173404; Tissue enhanced (brain, pituitary gland).
DR MIM; 600010; gene.
DR neXtProt; NX_Q01101; -.
DR OpenTargets; ENSG00000173404; -.
DR PharmGKB; PA29897; -.
DR VEuPathDB; HostDB:ENSG00000173404; -.
DR eggNOG; KOG3993; Eukaryota.
DR GeneTree; ENSGT00940000162552; -.
DR HOGENOM; CLU_033476_1_0_1; -.
DR InParanoid; Q01101; -.
DR OMA; REHEKHK; -.
DR OrthoDB; 1306883at2759; -.
DR PhylomeDB; Q01101; -.
DR TreeFam; TF320538; -.
DR PathwayCommons; Q01101; -.
DR Reactome; R-HSA-210746; Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells.
DR SignaLink; Q01101; -.
DR SIGNOR; Q01101; -.
DR BioGRID-ORCS; 3642; 12 hits in 1090 CRISPR screens.
DR GeneWiki; INSM1; -.
DR GenomeRNAi; 3642; -.
DR Pharos; Q01101; Tbio.
DR PRO; PR:Q01101; -.
DR Proteomes; UP000005640; Chromosome 20.
DR RNAct; Q01101; protein.
DR Bgee; ENSG00000173404; Expressed in type B pancreatic cell and 79 other tissues.
DR Genevisible; Q01101; HS.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0017053; C:transcription repressor complex; IDA:UniProtKB.
DR GO; GO:0031490; F:chromatin DNA binding; IDA:UniProtKB.
DR GO; GO:0030332; F:cyclin binding; IPI:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0042826; F:histone deacetylase binding; IPI:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0061104; P:adrenal chromaffin cell differentiation; ISS:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0016477; P:cell migration; IEA:Ensembl.
DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:UniProtKB.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0030182; P:neuron differentiation; IBA:GO_Central.
DR GO; GO:0003358; P:noradrenergic neuron development; ISS:UniProtKB.
DR GO; GO:0042421; P:norepinephrine biosynthetic process; ISS:UniProtKB.
DR GO; GO:0003310; P:pancreatic A cell differentiation; ISS:UniProtKB.
DR GO; GO:0045597; P:positive regulation of cell differentiation; ISS:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:2000179; P:positive regulation of neural precursor cell proliferation; ISS:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; IDA:UniProtKB.
DR GO; GO:0010564; P:regulation of cell cycle process; IBA:GO_Central.
DR GO; GO:0010468; P:regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IDA:UniProtKB.
DR GO; GO:0061549; P:sympathetic ganglion development; ISS:UniProtKB.
DR GO; GO:0060290; P:transdifferentiation; IDA:UniProtKB.
DR GO; GO:0003323; P:type B pancreatic cell development; IEA:Ensembl.
DR GO; GO:0003309; P:type B pancreatic cell differentiation; ISS:UniProtKB.
DR DisProt; DP01023; -.
DR IDEAL; IID00415; -.
DR InterPro; IPR042972; INSM1/2.
DR InterPro; IPR036236; Znf_C2H2_sf.
DR InterPro; IPR013087; Znf_C2H2_type.
DR PANTHER; PTHR15065; PTHR15065; 1.
DR Pfam; PF00096; zf-C2H2; 4.
DR SMART; SM00355; ZnF_C2H2; 5.
DR SUPFAM; SSF57667; SSF57667; 3.
DR PROSITE; PS00028; ZINC_FINGER_C2H2_1; 4.
DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 4.
PE 1: Evidence at protein level;
KW 3D-structure; Cell cycle; Developmental protein; Differentiation;
KW DNA-binding; Metal-binding; Neurogenesis; Nucleus; Reference proteome;
KW Repeat; Repressor; Transcription; Transcription regulation; Zinc;
KW Zinc-finger.
FT CHAIN 1..510
FT /note="Insulinoma-associated protein 1"
FT /id="PRO_0000047268"
FT ZN_FING 267..287
FT /note="C2H2-type 1; atypical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT ZN_FING 295..317
FT /note="C2H2-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT ZN_FING 367..389
FT /note="C2H2-type 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT ZN_FING 441..464
FT /note="C2H2-type 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT ZN_FING 469..492
FT /note="C2H2-type 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT REGION 1..110
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1..20
FT /note="SNAG domain"
FT /evidence="ECO:0000250|UniProtKB:Q63ZV0"
FT REGION 2..7
FT /note="Required and sufficient for interaction with KDM1A"
FT /evidence="ECO:0000269|PubMed:23721412"
FT REGION 43..58
FT /note="Necessary for interaction with CCND1"
FT REGION 176..226
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 315..362
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 41..61
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 183..211
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MUTAGEN 43..58
FT /note="PPAPSPVPGPLPPPPP->LLALSLVLGLLLLLLL: Inhibits weakly
FT translational repression activity. Inhibits interaction
FT with CCND1 and cell cycle arrest."
FT /evidence="ECO:0000269|PubMed:19124461"
FT HELIX 3..5
FT /evidence="ECO:0007829|PDB:3ZMS"
FT STRAND 449..452
FT /evidence="ECO:0007829|PDB:2LV2"
FT HELIX 453..461
FT /evidence="ECO:0007829|PDB:2LV2"
FT STRAND 466..470
FT /evidence="ECO:0007829|PDB:2LV2"
FT STRAND 477..480
FT /evidence="ECO:0007829|PDB:2LV2"
FT HELIX 481..489
FT /evidence="ECO:0007829|PDB:2LV2"
SQ SEQUENCE 510 AA; 52923 MW; 22D4E97696397365 CRC64;
MPRGFLVKRS KKSTPVSYRV RGGEDGDRAL LLSPSCGGAR AEPPAPSPVP GPLPPPPPAE
RAHAALAAAL ACAPGPQPPP QGPRAAHFGN PEAAHPAPLY SPTRPVSREH EKHKYFERSF
NLGSPVSAES FPTPAALLGG GGGGGASGAG GGGTCGGDPL LFAPAELKMG TAFSAGAEAA
RGPGPGPPLP PAAALRPPGK RPPPPTAAEP PAKAVKAPGA KKPKAIRKLH FEDEVTTSPV
LGLKIKEGPV EAPRGRAGGA ARPLGEFICQ LCKEEYADPF ALAQHKCSRI VRVEYRCPEC
AKVFSCPANL ASHRRWHKPR PAPAAARAPE PEAAARAEAR EAPGGGSDRD TPSPGGVSES
GSEDGLYECH HCAKKFRRQA YLRKHLLAHH QALQAKGAPL APPAEDLLAL YPGPDEKAPQ
EAAGDGEGAG VLGLSASAEC HLCPVCGESF ASKGAQERHL RLLHAAQVFP CKYCPATFYS
SPGLTRHINK CHPSENRQVI LLQVPVRPAC
