IGF1R

The insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase involved in several biological processes including cell proliferation, differentiation, DNA repair, and cell survival. This a disulfide-linked heterotetrameric transmembrane protein consisting of two α and two β subunits, and among which, the α subunit is extracellular while the β subunit has an extracellular domain, a transmembrane domain and a cytoplasmic tyrosine kinase domain. IGF1R signalling pathway is activated in the mammalian nervous system from early developmental stages. Its major effect on developing neural cells is to promote their growth and survival. This pathway can integrate its action with signalling pathways of growth and morphogenetic factors that induce cell fate specification and selective expansion of specified neural cell subsets.

IGF1R Related Areas

Enzyme>>Protein Kinase>>Receptor Tyrosine Kinase>>IGF1R/CD221

Signal Transduction>>Protein Kinase>>Receptor Tyrosine Kinase>>IGF1R/CD221

Cancer>>Cancer Biomarkers>>IGF1R/CD221

Cancer>>Growth Factor & Receptor>>IGF System>>IGF1R/CD221

Cancer>>Growth Factor & Receptor>>Receptor Tyrosine Kinase>>IGF1R/CD221

Immunology>>Cluster of Differentiation>>Dendritic Cell CD Antigen>>Dendritic Cell Adhesion>>IGF1R/CD221

IGF1R Alternative Names

IGF1R, IGFIR, CD221, JTK13, MGC142170, MGC142172, MGC18216 [Homo sapiens]

Igf1r, A330103N21Rik, CD221, D930020L01, IGF-1R, hyft [Mus musculus]

Summaries for IGF1R

Entrez Gene summary for IGF1R:

This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The IGF1R plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. IGF1R is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival.

Wikipedia summary for IGF1R:

The Insulin-like Growth Factor 1 (IGF-1) Receptor is a transmembrane receptor that is activated by IGF-1 and by the related growth factor IGF-2. IGF1R belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in molecular structure to insulin. IGF-1 plays an important role in growth and continues to have anabolic effects in adults - meaning that it can induce hypertrophy of skeletal muscle and other target tissues. Mice lacking the IGF1R die late in development, and show a dramatic reduction in body mass, testifying to the strong growth-promoting effect of this receptor. Mice carrying only one functional copy of igf1r are normal, but exhibit a ~15% decrease in body mass.

Human IGF1R Protein General Information

 

• Protein names: Insulin-like growth factor I receptor, Short name=IGF-I receptor
• Sequence length: 1367 AA.
• Domain
• Sequence similarities: IGF1R belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily. IGF1R contains 3 fibronectin type-III domains. IGF1R contains 1 protein kinase domain.
• Post-translational modification: IGF1R is autophosphorylated on tyrosine residues in response to ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Autophosphorylation occurs in a sequential manner; Tyr-1165 is predominantly phosphorylated first, followed by phosphorylation of Tyr-1161 and Tyr-1166. While every single phosphorylation increases kinase activity, all three tyrosine residues in the kinase activation loop (Tyr-1165, Tyr-1161 and Tyr-1166) have to be phosphorylated for optimal activity.
• Subunit structure: Tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains contribute to the formation of the ligand-binding domain, while the beta chain carries the kinase domain. IGF1R interacts with PIK3R1 and with the PTB/PID domains of IRS1 and SHC1 in vitro when autophosphorylated on tyrosine residues. IGF1R forms a hybrid receptor with INSR, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. IGF1R interacts with ARRB1 and ARRB2. Interacts with GRB10. IGF1R interacts with GNB2L1/RACK1. IGF1R interacts with SOCS1, SOCS2 and SOCS3. Interacts with 14-3-3 proteins. IGF1R interacts with NMD2. Interacts with MAP3K5. Interacts with STAT3.
• Subcellular location: Membrane; Single-pass type I membrane protein.
• Tissue specificity: IGF1R is found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). IGF1R is expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney.
• Involvement in disease: DEFects in IGF1R are a cause of insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]. It is a disorder characterized by intrauterine growth retardation and poor postnatal growth accompanied with increased plasma IGF1.
• Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
• Enzyme regulation: IGF1R is activated by autophosphorylation at Tyr-1165, Tyr-1161 and Tyr-1166 on the kinase activation loop; phosphorylation at all three tyrosine residues is required for optimal kinase activity. Inhibited by MSC1609119A-1, BMS-754807, PQIP, benzimidazole pyridinone, isoquinolinedione, bis-azaindole, 3-cyanoquinoline, 2,4-bis-arylamino-1,3-pyrimidine, pyrrolopyrimidine, pyrrole-5-carboxaldehyde, picropodophyllin (PPP), tyrphostin derivatives. While most inhibitors bind to the ATP binding pocket, MSC1609119A-1 functions as allosteric inhibitor and binds close to the DFG motif and the activation loop.
• Sequence caution: The sequence BAG11657.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

General information above from UniProt

Function for IGF1R Protein

UniProtKB:

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.

Genatlas:

• insulin-like growth factor 1, receptor with high affinity
• receptor tyrosine kinase, class II, with potent mitogenic, antiapoptotic and transforming activities required for oncogenic transformation
• IGF1R activates PI3K
• IGF1R is positive regulation of cell proliferation
• IGF1R inhibits MAP3K5 (complexed with, in perinuclear structures) and then supresses stimulation of JNK/p38 pathway and induction of programmed cell death
• IGF1R binds its ligand and then initiates metabolic cascades resulting in stimulation of protein synthesis, glucose intake, glycogen synthesis or lipid storage
• activation of IGF1R prevents high glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis (Pubmed 19406106)

Homology for human IGF1R

• homolog to murine Igf1r

Phenotype Information for IGF1R

• Gene/Locus: IGF1R
• Phenotype: Insulin-like growth factor I, resistance to

Phenotype Information for IGF1R from OMIM (Online Mendelian Inheritance in Man)

Drugs for IGF1R

Target	Drug Name	Disease	Drug Status
IGF1R	Mecasermin	IGF-1 deficiency	Approved
IGF1R	AEW-541	Various cancers, multiple myeloma	Phase I
IGF1R	AMG 479	Cancers	Phase II
IGF1R	Figitumumab	Gastrointestinal Cancers; Genitourinary; Ewing's Sarcoma; Small Cell Lung Cancer; Breast Cancer (Biologic)	Phase II
IGF1R	Figitumumab	Non-Small Cell Lung Cancer (Biologic)	Phase III
IGF1R	MK-0646	Cancer	Phase II
IGF1R	R1507	NSCLC, Ewing's sarcoma and metastatic breast cancer	Suspended in Phase II

Drugs for IGF1R from TTD (Therapeutic Targets Database)