IGF1R_PIG
ID IGF1R_PIG Reviewed; 304 AA.
AC Q29000; Q28951;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 2.
DT 03-AUG-2022, entry version 147.
DE RecName: Full=Insulin-like growth factor 1 receptor;
DE EC=2.7.10.1;
DE AltName: Full=Insulin-like growth factor I receptor;
DE Short=IGF-I receptor;
DE AltName: CD_antigen=CD221;
DE Flags: Fragments;
GN Name=IGF1R;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-186.
RC TISSUE=Skeletal muscle;
RA Matteri R.L., Anderson J.E., Prather R.S.;
RL Submitted (JUN-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 187-304.
RC TISSUE=Conceptus membrane;
RX PubMed=7649105; DOI=10.1210/endo.136.9.7649105;
RA Green M.L., Simmen R.C.M., Simmen F.A.;
RT "Developmental regulation of steroidogenic enzyme gene expression in the
RT periimplantation porcine conceptus: a paracrine role for insulin-like
RT growth factor-I.";
RL Endocrinology 136:3961-3970(1995).
CC -!- FUNCTION: Receptor tyrosine kinase which mediates actions of insulin-
CC like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and
CC insulin (INS) with a lower affinity. The activated IGF1R is involved in
CC cell growth and survival control. IGF1R is crucial for tumor
CC transformation and survival of malignant cell. Ligand binding activates
CC the receptor kinase, leading to receptor autophosphorylation, and
CC tyrosines phosphorylation of multiple substrates, that function as
CC signaling adapter proteins including, the insulin-receptor substrates
CC (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins
CC lead to the activation of two main signaling pathways: the PI3K-AKT/PKB
CC pathway and the Ras-MAPK pathway. The result of activating the MAPK
CC pathway is increased cellular proliferation, whereas activating the
CC PI3K pathway inhibits apoptosis and stimulates protein synthesis.
CC Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K
CC (PIK3R1), leading to activation of several downstream substrates,
CC including protein AKT/PKB. AKT phosphorylation, in turn, enhances
CC protein synthesis through mTOR activation and triggers the
CC antiapoptotic effects of IGFIR through phosphorylation and inactivation
CC of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS
CC by phosphorylated IRS1 or Shc leads to recruitment of Ras and
CC activation of the ras-MAPK pathway. In addition to these two main
CC signaling pathways IGF1R signals also through the Janus kinase/signal
CC transducer and activator of transcription pathway (JAK/STAT).
CC Phosphorylation of JAK proteins can lead to phosphorylation/activation
CC of signal transducers and activators of transcription (STAT) proteins.
CC In particular activation of STAT3, may be essential for the
CC transforming activity of IGF1R. The JAK/STAT pathway activates gene
CC transcription and may be responsible for the transforming activity. JNK
CC kinases can also be activated by the IGF1R. IGF1 exerts inhibiting
CC activities on JNK activation via phosphorylation and inhibition of
CC MAP3K5/ASK1, which is able to directly associate with the IGF1R (By
CC similarity). When present in a hybrid receptor with INSR, binds IGF1
CC (By similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: Activated by autophosphorylation at tyrosines in
CC the kinase activation loop; phosphorylation at all three tyrosine
CC residues is required for optimal kinase activity. Inhibited by
CC MSC1609119A-1, BMS-754807, PQIP, benzimidazole pyridinone,
CC isoquinolinedione, bis-azaindole, 3-cyanoquinoline, 2,4-bis-arylamino-
CC 1,3-pyrimidine, pyrrolopyrimidine, pyrrole-5-carboxaldehyde,
CC picropodophyllin (PPP), tyrphostin derivatives. While most inhibitors
CC bind to the ATP binding pocket, MSC1609119A-1 functions as allosteric
CC inhibitor and binds close to the DFG motif and the activation loop (By
CC similarity). {ECO:0000250}.
CC -!- SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide
CC bonds. The alpha chains contribute to the formation of the ligand-
CC binding domain, while the beta chain carries the kinase domain. Forms a
CC hybrid receptor with INSR, the hybrid is a tetramer consisting of 1
CC alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain
CC of IGF1R. Interacts with ARRB1 and ARRB2. Interacts with GRB10.
CC Interacts with RACK1 (By similarity). Interacts with SOCS1, SOCS2 and
CC SOCS3 (By similarity). Interacts with 14-3-3 proteins (By similarity).
CC Interacts with NMD2 (By similarity). Interacts with MAP3K5 (By
CC similarity). Interacts with STAT3. Found in a ternary complex with IGF1
CC and ITGAV:ITGB3 or ITGA6:ITGB4 (By similarity). Interacts (nascent
CC precursor form) with ZFAND2B (By similarity).
CC {ECO:0000250|UniProtKB:P08069}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I
CC membrane protein {ECO:0000250}.
CC -!- PTM: Autophosphorylated on tyrosine residues in response to ligand
CC binding. Autophosphorylation occurs in trans, i.e. one subunit of the
CC dimeric receptor phosphorylates tyrosine residues on the other subunit.
CC Autophosphorylation occurs in a sequential manner. While every single
CC phosphorylation increases kinase activity, all three tyrosine residues
CC in the kinase activation loop have to be phosphorylated for optimal
CC activity. Can be autophosphorylated at additional tyrosine residues (in
CC vitro). Autophosphorylated is followed by phosphorylation of
CC juxtamembrane tyrosines and C-terminal serines (By similarity).
CC Phosphorylation of Ser-225 by GSK-3beta restrains kinase activity and
CC promotes cell surface expression, it requires a priming phosphorylation
CC at Ser-229. Dephosphorylated by PTPN1 (By similarity). {ECO:0000250}.
CC -!- PTM: Polyubiquitinated in the activation loop through both 'Lys-48' and
CC 'Lys-29' linkages, promoting receptor endocytosis and subsequent
CC degradation by the proteasome. Ubiquitination is facilitated by pre-
CC existing phosphorylation (By similarity). {ECO:0000250}.
CC -!- PTM: Sumoylated with SUMO1. {ECO:0000250}.
CC -!- PTM: Controlled by regulated intramembrane proteolysis (RIP). Undergoes
CC metalloprotease-dependent constitutive ectodomain shedding to produce a
CC membrane-anchored 52 kDa C-Terminal fragment which is further processed
CC by presenilin gamma-secretase to yield an intracellular 50 kDa fragment
CC (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; U58370; AAB02578.1; -; mRNA.
DR EMBL; U15445; AAB49731.1; -; mRNA.
DR AlphaFoldDB; Q29000; -.
DR SMR; Q29000; -.
DR PaxDb; Q29000; -.
DR PeptideAtlas; Q29000; -.
DR PRIDE; Q29000; -.
DR eggNOG; KOG4258; Eukaryota.
DR InParanoid; Q29000; -.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0043409; P:negative regulation of MAPK cascade; ISS:UniProtKB.
DR GO; GO:0046328; P:regulation of JNK cascade; ISS:UniProtKB.
DR CDD; cd00063; FN3; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR Pfam; PF00041; fn3; 1.
DR SMART; SM00060; FN3; 1.
DR SUPFAM; SSF49265; SSF49265; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50853; FN3; 2.
PE 2: Evidence at transcript level;
KW ATP-binding; Cell membrane; Disulfide bond; Glycoprotein; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Receptor; Reference proteome; Repeat;
KW Transferase; Transmembrane; Transmembrane helix; Tyrosine-protein kinase;
KW Ubl conjugation.
FT CHAIN <1..>304
FT /note="Insulin-like growth factor 1 receptor"
FT /id="PRO_0000058926"
FT TOPO_DOM <1..147
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 148..168
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 169..>304
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN <1..43
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 49..142
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT REGION 231..304
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 225
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:Q60751"
FT MOD_RES 229
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q60751"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 128
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT NON_CONS 186..187
FT /evidence="ECO:0000305"
FT NON_TER 1
FT NON_TER 304
SQ SEQUENCE 304 AA; 34615 MW; E026E01215FC3AB8 CRC64;
ERTVISNLRP FTLYRIDIHS CNHEAEKLGC SASNFVFART MPAEGADDIP GPVTWEPRPE
NSIFLKWPEP ENPNGLILMY EIKYGSQVED QRECVSRQEY RKYGGAKLNR LNPGNYTARI
QATSLSGNGS WTEPVFFYVQ AKTTYENFIH LIIALPVAVL LIVGGLVIML YVFHRKRNNS
RLGNGVMLFE LMRMCWQYNP KMRPSFLEII SSIKDEMEPG FREVSFYYSE ENKPPEPEEL
DLEPENMESV PLDPSASSSS LPLPDRHSGH KAENGPGPGV LVLRASFDER QPYAHMNGGR
KNER
