ID   IGF2_RAT                Reviewed;         180 AA.
AC   P01346;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   20-MAR-1987, sequence version 1.
DT   24-JAN-2024, entry version 180.
DE   RecName: Full=Insulin-like growth factor II;
DE            Short=IGF-II;
DE   AltName: Full=Multiplication-stimulating activity;
DE            Short=MSA;
DE   AltName: Full=Multiplication-stimulating polypeptide;
DE   Contains:
DE     RecName: Full=Insulin-like growth factor II;
DE   Contains:
DE     RecName: Full=Preptin;
DE   Flags: Precursor;
GN   Name=Igf2; Synonyms=Igf-2;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=BRL-3A;
RX   PubMed=6382022; DOI=10.1038/310777a0;
RA   Dull T.J., Gray A., Hayflick J.S., Ullrich A.;
RT   "Insulin-like growth factor II precursor gene organization in relation to
RT   insulin gene family.";
RL   Nature 310:777-781(1984).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=Buffalo;
RX   PubMed=3889836; DOI=10.1093/nar/13.4.1119;
RA   Soares M.B., Ishii D.N., Efstratiadis A.;
RT   "Developmental and tissue-specific expression of a family of transcripts
RT   related to rat insulin-like growth factor II mRNA.";
RL   Nucleic Acids Res. 13:1119-1134(1985).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=2438416; DOI=10.1016/0022-2836(86)90025-2;
RA   Soares M.B., Turken A., Ishii D.N., Mills L., Episkopou V., Cotter S.,
RA   Zeitlin S., Efstratiadis A.;
RT   "Rat insulin-like growth factor II gene. A single gene with two promoters
RT   expressing a multitranscript family.";
RL   J. Mol. Biol. 192:737-752(1986).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=3023383; DOI=10.1016/s0021-9258(19)76010-4;
RA   Frunzio R., Chiariotti L., Brown A.L., Graham D.E., Rechler M.M.,
RA   Bruni C.B.;
RT   "Structure and expression of the rat insulin-like growth factor II (rIGF-
RT   II) gene. rIGF-II RNAs are transcribed from two promoters.";
RL   J. Biol. Chem. 261:17138-17149(1986).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=3167060; DOI=10.1016/0167-4781(88)90138-8;
RA   Ueno T., Takahashi K., Matsuguchi T., Endo H., Yamamoto M.;
RT   "Transcriptional deviation of the rat insulin-like growth factor II gene
RT   initiated at three alternative leader-exons between neonatal tissues and
RT   ascites hepatomas.";
RL   Biochim. Biophys. Acta 950:411-419(1988).
RN   [6]
RP   NUCLEOTIDE SEQUENCE OF 62-180.
RX   PubMed=6390212; DOI=10.1038/312277a0;
RA   Whitfield H.J., Bruni C.B., Frunzio R., Terrell J.E., Nissley S.P.,
RA   Rechler M.M.;
RT   "Isolation of a cDNA clone encoding rat insulin-like growth factor-II
RT   precursor.";
RL   Nature 312:277-280(1984).
RN   [7]
RP   NUCLEOTIDE SEQUENCE OF 103-180.
RX   PubMed=3221878; DOI=10.1210/mend-2-11-1115;
RA   Chiariotti L., Brown A.L., Frunzio R., Clemmons D.R., Rechler M.M.,
RA   Bruni C.B.;
RT   "Structure of the rat insulin-like growth factor II transcriptional unit:
RT   heterogeneous transcripts are generated from two promoters by use of
RT   multiple polyadenylation sites and differential ribonucleic acid
RT   splicing.";
RL   Mol. Endocrinol. 2:1115-1126(1988).
RN   [8]
RP   PROTEIN SEQUENCE OF 25-91.
RX   PubMed=7016879; DOI=10.1016/s0021-9258(19)69071-x;
RA   Marquardt H., Todaro G.J., Henderson L.E., Oroszlan S.;
RT   "Purification and primary structure of a polypeptide with multiplication-
RT   stimulating activity from rat liver cell cultures. Homology with human
RT   insulin-like growth factor II.";
RL   J. Biol. Chem. 256:6859-6865(1981).
RN   [9]
RP   OSTEOGENIC FUNCTION OF PREPTIN.
RX   PubMed=16912056; DOI=10.1152/ajpendo.00642.2005;
RA   Cornish J., Callon K.E., Bava U., Watson M., Xu X., Lin J.M., Chan V.A.,
RA   Grey A.B., Naot D., Buchanan C.M., Cooper G.J., Reid I.R.;
RT   "Preptin, another peptide product of the pancreatic beta-cell, is
RT   osteogenic in vitro and in vivo.";
RL   Am. J. Physiol. 292:E117-E122(2007).
CC   -!- FUNCTION: The insulin-like growth factors possess growth-promoting
CC       activity (By similarity). Major fetal growth hormone in mammals. Plays
CC       a key role in regulating fetoplacental development. IGF2 is influenced
CC       by placental lactogen. Also involved in tissue differentiation. In
CC       adults, involved in glucose metabolism in adipose tissue, skeletal
CC       muscle and liver. Acts as a ligand for integrin which is required for
CC       IGF2 signaling. Positively regulates myogenic transcription factor
CC       MYOD1 function by facilitating the recruitment of transcriptional
CC       coactivators, thereby controlling muscle terminal differentiation (By
CC       similarity). Inhibits myoblast differentiation and modulates metabolism
CC       via increasing the mitochondrial respiration rate (By similarity).
CC       {ECO:0000250|UniProtKB:P01344, ECO:0000250|UniProtKB:P09535}.
CC   -!- FUNCTION: Preptin undergoes glucose-mediated co-secretion with insulin,
CC       and acts as a physiological amplifier of glucose-mediated insulin
CC       secretion. Exhibits osteogenic properties by increasing osteoblast
CC       mitogenic activity through phosphoactivation of MAPK1 and MAPK3.
CC       {ECO:0000250|UniProtKB:P01344, ECO:0000250|UniProtKB:P09535}.
CC   -!- SUBUNIT: Interacts with MYORG; this interaction is required for IGF2
CC       secretion. Interacts with integrins ITGAV:ITGB3 and ITGA6:ITGB4;
CC       integrin-binding is required for IGF2 signaling.
CC       {ECO:0000250|UniProtKB:P01344, ECO:0000250|UniProtKB:P09535}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P01344,
CC       ECO:0000250|UniProtKB:P09535}.
CC   -!- PTM: Proteolytically processed by PCSK4, proIGF2 is cleaved at Arg-128
CC       and Arg-92 to generate big-IGF2 and mature IGF2.
CC       {ECO:0000250|UniProtKB:P01344}.
CC   -!- MISCELLANEOUS: The IGF2 locus is imprinted. Paternal inherited gene is
CC       expressed, while the maternal inherited gene is imprinted, hence
CC       silenced. {ECO:0000250|UniProtKB:P09535}.
CC   -!- SIMILARITY: Belongs to the insulin family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=CAA25427.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC       Sequence=CAA25429.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; X00911; CAA25428.1; -; mRNA.
DR   EMBL; X00911; CAA25427.1; ALT_INIT; mRNA.
DR   EMBL; X00911; CAA25429.1; ALT_INIT; mRNA.
DR   EMBL; X02213; CAA26136.1; -; mRNA.
DR   EMBL; X13101; CAA31493.1; -; mRNA.
DR   EMBL; X14833; CAA32942.1; -; mRNA.
DR   EMBL; X14834; CAA32943.1; -; mRNA.
DR   EMBL; M13871; AAB95624.1; -; Genomic_DNA.
DR   EMBL; M13869; AAB95624.1; JOINED; Genomic_DNA.
DR   EMBL; M13870; AAB95624.1; JOINED; Genomic_DNA.
DR   EMBL; M29880; AAA41391.1; -; Genomic_DNA.
DR   EMBL; M29879; AAA41391.1; JOINED; Genomic_DNA.
DR   EMBL; M30273; AAA41432.1; -; mRNA.
DR   EMBL; M31221; AAA42046.1; -; Genomic_DNA.
DR   PIR; A25350; IGRT2.
DR   RefSeq; NP_001177091.1; NM_001190162.1.
DR   RefSeq; NP_001177092.1; NM_001190163.1.
DR   RefSeq; NP_113699.2; NM_031511.2.
DR   RefSeq; XP_006230727.1; XM_006230665.2.
DR   AlphaFoldDB; P01346; -.
DR   SMR; P01346; -.
DR   IntAct; P01346; 1.
DR   STRING; 10116.ENSRNOP00000068633; -.
DR   PhosphoSitePlus; P01346; -.
DR   PaxDb; 10116-ENSRNOP00000047037; -.
DR   ABCD; P01346; 1 sequenced antibody.
DR   GeneID; 24483; -.
DR   KEGG; rno:24483; -.
DR   UCSC; RGD:2870; rat.
DR   AGR; RGD:2870; -.
DR   CTD; 3481; -.
DR   RGD; 2870; Igf2.
DR   eggNOG; ENOG502S0I0; Eukaryota.
DR   InParanoid; P01346; -.
DR   OrthoDB; 5402912at2759; -.
DR   PhylomeDB; P01346; -.
DR   TreeFam; TF332820; -.
DR   Reactome; R-RNO-114608; Platelet degranulation.
DR   Reactome; R-RNO-2404192; Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R).
DR   Reactome; R-RNO-2428928; IRS-related events triggered by IGF1R.
DR   Reactome; R-RNO-2428933; SHC-related events triggered by IGF1R.
DR   Reactome; R-RNO-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR   PRO; PR:P01346; -.
DR   Proteomes; UP000002494; Chromosome 1.
DR   Bgee; ENSRNOG00000020369; Expressed in quadriceps femoris and 18 other cell types or tissues.
DR   ExpressionAtlas; P01346; baseline and differential.
DR   GO; GO:0005615; C:extracellular space; IDA:RGD.
DR   GO; GO:0008083; F:growth factor activity; ISO:RGD.
DR   GO; GO:0005179; F:hormone activity; IEA:UniProtKB-KW.
DR   GO; GO:0005158; F:insulin receptor binding; ISO:RGD.
DR   GO; GO:0005159; F:insulin-like growth factor receptor binding; ISO:RGD.
DR   GO; GO:0005178; F:integrin binding; ISS:UniProtKB.
DR   GO; GO:0043539; F:protein serine/threonine kinase activator activity; ISO:RGD.
DR   GO; GO:0048018; F:receptor ligand activity; ISO:RGD.
DR   GO; GO:0030297; F:transmembrane receptor protein tyrosine kinase activator activity; ISO:RGD.
DR   GO; GO:0009887; P:animal organ morphogenesis; ISO:RGD.
DR   GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:RGD.
DR   GO; GO:0001892; P:embryonic placenta development; ISS:UniProtKB.
DR   GO; GO:0060669; P:embryonic placenta morphogenesis; ISO:RGD.
DR   GO; GO:0031017; P:exocrine pancreas development; ISO:RGD.
DR   GO; GO:0007565; P:female pregnancy; IEP:RGD.
DR   GO; GO:0006006; P:glucose metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0001701; P:in utero embryonic development; ISO:RGD.
DR   GO; GO:0008286; P:insulin receptor signaling pathway; ISO:RGD.
DR   GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; ISO:RGD.
DR   GO; GO:0007613; P:memory; IMP:RGD.
DR   GO; GO:0051148; P:negative regulation of muscle cell differentiation; ISS:UniProtKB.
DR   GO; GO:0045953; P:negative regulation of natural killer cell mediated cytotoxicity; IDA:RGD.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR   GO; GO:0001649; P:osteoblast differentiation; ISO:RGD.
DR   GO; GO:0042104; P:positive regulation of activated T cell proliferation; ISO:RGD.
DR   GO; GO:0045766; P:positive regulation of angiogenesis; IGI:BHF-UCL.
DR   GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IGI:BHF-UCL.
DR   GO; GO:0051781; P:positive regulation of cell division; IEA:UniProtKB-KW.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
DR   GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; ISO:RGD.
DR   GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; ISO:RGD.
DR   GO; GO:0043410; P:positive regulation of MAPK cascade; ISO:RGD.
DR   GO; GO:0045840; P:positive regulation of mitotic nuclear division; ISO:RGD.
DR   GO; GO:0040018; P:positive regulation of multicellular organism growth; ISO:RGD.
DR   GO; GO:0046622; P:positive regulation of organ growth; ISO:RGD.
DR   GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IBA:GO_Central.
DR   GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISO:RGD.
DR   GO; GO:0048633; P:positive regulation of skeletal muscle tissue growth; ISO:RGD.
DR   GO; GO:0090031; P:positive regulation of steroid hormone biosynthetic process; IDA:BHF-UCL.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISO:RGD.
DR   GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; IGI:BHF-UCL.
DR   GO; GO:0051147; P:regulation of muscle cell differentiation; ISS:UniProtKB.
DR   GO; GO:0032355; P:response to estradiol; IEP:RGD.
DR   GO; GO:0045471; P:response to ethanol; IEP:RGD.
DR   GO; GO:0035094; P:response to nicotine; IDA:RGD.
DR   GO; GO:0031667; P:response to nutrient levels; IEP:RGD.
DR   GO; GO:0014070; P:response to organic cyclic compound; IDA:RGD.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IDA:RGD.
DR   GO; GO:0060720; P:spongiotrophoblast cell proliferation; ISO:RGD.
DR   GO; GO:0051146; P:striated muscle cell differentiation; ISO:RGD.
DR   CDD; cd04368; IlGF; 1.
DR   Gene3D; 1.10.100.10; Insulin-like; 1.
DR   InterPro; IPR022334; IGF2.
DR   InterPro; IPR013576; IGF2_C.
DR   InterPro; IPR016179; Insulin-like.
DR   InterPro; IPR022350; Insulin-like_growth_factor.
DR   InterPro; IPR036438; Insulin-like_sf.
DR   InterPro; IPR022353; Insulin_CS.
DR   InterPro; IPR022352; Insulin_family.
DR   PANTHER; PTHR46886; INSULIN-LIKE GROWTH FACTOR II; 1.
DR   PANTHER; PTHR46886:SF1; INSULIN-LIKE GROWTH FACTOR II; 1.
DR   Pfam; PF08365; IGF2_C; 1.
DR   Pfam; PF00049; Insulin; 2.
DR   PRINTS; PR02002; INSLNLIKEGF.
DR   PRINTS; PR02006; INSLNLIKEGF2.
DR   PRINTS; PR00276; INSULINFAMLY.
DR   SMART; SM00078; IlGF; 1.
DR   SUPFAM; SSF56994; Insulin-like; 1.
DR   PROSITE; PS00262; INSULIN; 1.
DR   Genevisible; P01346; RN.
PE   1: Evidence at protein level;
KW   Carbohydrate metabolism; Cleavage on pair of basic residues;
KW   Direct protein sequencing; Disulfide bond; Glucose metabolism;
KW   Growth factor; Hormone; Mitogen; Osteogenesis; Reference proteome;
KW   Secreted; Signal.
FT   SIGNAL          1..24
FT                   /evidence="ECO:0000269|PubMed:7016879"
FT   CHAIN           25..91
FT                   /note="Insulin-like growth factor II"
FT                   /id="PRO_0000015729"
FT   PROPEP          92..180
FT                   /note="E peptide"
FT                   /id="PRO_0000015730"
FT   PEPTIDE         93..126
FT                   /note="Preptin"
FT                   /id="PRO_0000370380"
FT   REGION          25..52
FT                   /note="B"
FT   REGION          53..64
FT                   /note="C"
FT   REGION          65..85
FT                   /note="A"
FT   REGION          86..91
FT                   /note="D"
FT   REGION          160..180
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            48
FT                   /note="Important for interaction with integrin"
FT                   /evidence="ECO:0000250|UniProtKB:P01344"
FT   SITE            58
FT                   /note="Important for interaction with integrin"
FT                   /evidence="ECO:0000250|UniProtKB:P01344"
FT   SITE            61
FT                   /note="Important for interaction with integrin"
FT                   /evidence="ECO:0000250|UniProtKB:P01344"
FT   SITE            62
FT                   /note="Important for interaction with integrin"
FT                   /evidence="ECO:0000250|UniProtKB:P01344"
FT   DISULFID        33..71
FT                   /evidence="ECO:0000250"
FT   DISULFID        45..84
FT                   /evidence="ECO:0000250"
FT   DISULFID        70..75
FT                   /evidence="ECO:0000250"
FT   CONFLICT        1..8
FT                   /note="Missing (in Ref. 2)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        57
FT                   /note="S -> G (in Ref. 3)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   180 AA;  20086 MW;  AF12B4EEC0DBCC34 CRC64;
     MGIPVGKSML VLLISLAFAL CCIAAYRPSE TLCGGELVDT LQFVCSDRGF YFSRPSSRAN
     RRSRGIVEEC CFRSCDLALL ETYCATPAKS ERDVSTSQAV LPDDFPRYPV GKFFKFDTWR
     QSAGRLRRGL PALLRARRGR MLAKELEAFR EAKRHRPLIV LPPKDPAHGG ASSEMSSNHQ
//