insulin-like growth factor receptor signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by a ligand binding to an insulin-like growth factor receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:ceb]

The Insulin-like Growth Factor Receptor (IGF1R) signaling pathway is a complex cascade of molecular events triggered by the binding of insulin-like growth factors (IGFs) to their cognate receptor, IGF1R. This pathway plays a crucial role in regulating cell growth, proliferation, differentiation, and survival, with profound implications for normal development and disease progression.

The pathway begins when IGF-I or IGF-II ligands bind to the extracellular alpha-subunits of IGF1R, a transmembrane receptor tyrosine kinase. Ligand binding initiates receptor dimerization and autophosphorylation of tyrosine residues within the intracellular kinase domain. This phosphorylation event creates docking sites for a cascade of downstream signaling molecules, including the Insulin Receptor Substrate (IRS) proteins.

IRS proteins act as adaptor molecules, bridging IGF1R to various signaling pathways, including the Ras-mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.

The Ras/MAPK pathway is activated through the recruitment of the Grb2 adaptor protein and the Son of Sevenless (SOS) guanine nucleotide exchange factor to the phosphorylated IRS proteins. This leads to the activation of Ras, a small GTPase, which subsequently activates the MAPK cascade, ultimately culminating in the phosphorylation and activation of transcription factors like Elk-1 and c-Jun. These activated transcription factors regulate the expression of genes involved in cell proliferation and differentiation.

The PI3K/Akt pathway is initiated by the recruitment of PI3K to the phosphorylated IRS proteins. PI3K phosphorylates phosphatidylinositol (PIP2) to generate PIP3, which serves as a docking site for Akt. Akt is a serine/threonine kinase that is activated through phosphorylation by phosphoinositide-dependent kinase 1 (PDK1) and mTORC2. Activated Akt promotes cell survival, growth, and metabolism by phosphorylating various downstream targets, including glycogen synthase kinase 3 (GSK3), the forkhead transcription factor FOXO, and the mammalian target of rapamycin (mTOR).

The crosstalk between the Ras/MAPK and PI3K/Akt pathways allows for fine-tuning of IGF1R signaling. For example, Akt can phosphorylate and inactivate the MAPK kinase (MEK), thereby attenuating the Ras/MAPK pathway.

The IGF1R signaling pathway is tightly regulated by a variety of mechanisms, including feedback loops, protein phosphatases, and ubiquitin ligases. These mechanisms ensure that the pathway is activated only when necessary and that its activity is properly balanced.

Dysregulation of the IGF1R signaling pathway is implicated in a variety of human diseases, including cancer, diabetes, and neurodegenerative disorders. Excessive IGF1R signaling can promote cell growth and survival, contributing to tumor development. Conversely, impaired IGF1R signaling can lead to reduced growth and increased susceptibility to disease.

The IGF1R pathway represents a complex and tightly regulated network that plays a pivotal role in regulating cellular processes essential for normal development and health. Understanding this pathway is crucial for developing targeted therapies for a range of diseases.'
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Proteins (21)

Compounds (596)