IGF1R encodes for insulin growth factor receptors; overexpression can stop cell death by enhancing cell survival and is present in malignant tissues (R). 

     From NCBI Gene: Insulin-like growth factor 1 resistance toFrom UniProt: Insulin-like growth factor 1 resistance (IGF1RES): A disorder characterized by intrauterine growth retardation, poor postnatal growth and increased plasma IGF1 levels. [MIM:270450]

     From NCBI Gene: This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014] From UniProt: 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 .

The following transcription factors affect gene expression:

• NF-kappaB
• p53
• NF-kappaB1
• MEF-2A
• Sp1
• STAT1
• STAT1beta
• STAT1alpha

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.

Enzyme Regulation:

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.

Molecular Function:

• Protein Tyrosine Kinase Activity
• Insulin-Like Growth Factor-Activated Receptor Activity
• Insulin Receptor Binding
• Insulin-Like Growth Factor Binding
• Atp Binding
• Insulin-Like Growth Factor I Binding
• Identical Protein Binding
• Phosphatidylinositol 3-Kinase Binding
• Insulin Binding
• Insulin Receptor Substrate Binding

Biological Processes:

• Immune Response
• Signal Transduction
• Positive Regulation Of Cell Proliferation
• Insulin Receptor Signaling Pathway
• Phosphatidylinositol 3-Kinase Signaling
• Positive Regulation Of Cell Migration
• Peptidyl-Tyrosine Autophosphorylation
• Negative Regulation Of Apoptotic Process
• Positive Regulation Of Dna Replication
• Regulation Of Jnk Cascade
• Protein Autophosphorylation
• Insulin-Like Growth Factor Receptor Signaling Pathway
• Phosphatidylinositol-Mediated Signaling
• Protein Tetramerization
• Inactivation Of Mapkk Activity

Drug Bank:

• Insulin Regular
• Insulin Lispro
• Mecasermin
• Insulin Glargine