InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: IGF1R

Summary

InnateDB Protein

IDBP-31434.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

IGF1R

Protein Name

insulin-like growth factor 1 receptor

Synonyms

CD221; IGFIR; IGFR; JTK13;

Species

Homo sapiens

Ensembl Protein

ENSP00000268035

InnateDB Gene

IDBG-31432 (IGF1R)

Protein Structure

UniProt Annotation

Function

Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K- driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.

Subcellular Localization

Cell membrane {ECO:0000269PubMed:17524361}; Single-pass type I membrane protein {ECO:0000269PubMed:17524361}.

Disease Associations

Insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]: A disorder characterized by intrauterine growth retardation, poor postnatal growth and increased plasma IGF1 levels. {ECO:0000269PubMed:14657428, ECO:0000269PubMed:15928254}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney. {ECO:0000269PubMed:12019176, ECO:0000269PubMed:8247543, ECO:0000269PubMed:9202395, ECO:0000269PubMed:9355755}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 118 experimentally validated interaction(s) in this database.
They are also associated with 5 interaction(s) predicted by orthology.

Experimentally validated
Total	118 [view]
Protein-Protein	116 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	5 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0001965	G-protein alpha-subunit binding
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004714	transmembrane receptor protein tyrosine kinase activity
GO:0005010	insulin-like growth factor-activated receptor activity
GO:0005158	insulin receptor binding
GO:0005515	protein binding
GO:0005520	insulin-like growth factor binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0031994	insulin-like growth factor I binding
GO:0042802	identical protein binding
GO:0043548	phosphatidylinositol 3-kinase binding
GO:0043559	insulin binding
GO:0043560	insulin receptor substrate binding

Biological Process

GO:0006468	protein phosphorylation
GO:0006955	immune response
GO:0007165	signal transduction
GO:0007169	transmembrane receptor protein tyrosine kinase signaling pathway
GO:0007409	axonogenesis
GO:0007420	brain development
GO:0008284	positive regulation of cell proliferation
GO:0008286	insulin receptor signaling pathway
GO:0008544	epidermis development
GO:0009887	organ morphogenesis
GO:0010656	negative regulation of muscle cell apoptotic process
GO:0014065	phosphatidylinositol 3-kinase signaling
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0030010	establishment of cell polarity
GO:0030238	male sex determination
GO:0030335	positive regulation of cell migration
GO:0030879	mammary gland development
GO:0031017	exocrine pancreas development
GO:0031175	neuron projection development
GO:0032467	positive regulation of cytokinesis
GO:0033197	response to vitamin E
GO:0038083	peptidyl-tyrosine autophosphorylation
GO:0043066	negative regulation of apoptotic process
GO:0043409	negative regulation of MAPK cascade
GO:0043410	positive regulation of MAPK cascade
GO:0043433	negative regulation of sequence-specific DNA binding transcription factor activity
GO:0045087	innate immune response (InnateDB)
GO:0045740	positive regulation of DNA replication
GO:0045840	positive regulation of mitosis
GO:0046328	regulation of JNK cascade
GO:0046777	protein autophosphorylation
GO:0048009	insulin-like growth factor receptor signaling pathway
GO:0048015	phosphatidylinositol-mediated signaling
GO:0051054	positive regulation of DNA metabolic process
GO:0051262	protein tetramerization
GO:0051291	protein heterooligomerization
GO:0051389	inactivation of MAPKK activity
GO:0051897	positive regulation of protein kinase B signaling
GO:0051898	negative regulation of protein kinase B signaling
GO:0060740	prostate gland epithelium morphogenesis
GO:0090031	positive regulation of steroid hormone biosynthetic process

Cellular Component

GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0005901	caveola
GO:0016020	membrane
GO:0016021	integral component of membrane
GO:0043005	neuron projection
GO:0043231	intracellular membrane-bounded organelle
GO:0043235	receptor complex

Protein Structure and Domains

PDB ID

InterPro

IPR000494 EGF receptor, L domain
IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR003961 Fibronectin, type III
IPR006211 Furin-like cysteine-rich domain
IPR006212 Furin-like repeat
IPR009030 Insulin-like growth factor binding protein, N-terminal
IPR011009 Protein kinase-like domain
IPR016246 Tyrosine-protein kinase, insulin-like receptor
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF01030
PF00069
PF07714
PF00041
PF01108
PF00757

PRINTS

PR00109

PIRSF

PIRSF000620

SMART

SM00220
SM00060
SM00261
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References