Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis.
Hirofumi NagaoAshok Kumar JayaveluWeikang CaiHui PanJonathan M DreyfussThiago M BatistaBruna Brasil BrandaoMatthias MannC Ronald KahnPublished in: Nature communications (2023)
Insulin acts through the insulin receptor (IR) tyrosine kinase to exert its classical metabolic and mitogenic actions. Here, using receptors with either short or long deletion of the β-subunit or mutation of the kinase active site (K1030R), we have uncovered a second, previously unrecognized IR signaling pathway that is intracellular domain-dependent, but ligand and tyrosine kinase-independent (LYK-I). These LYK-I actions of the IR are linked to changes in phosphorylation of a network of proteins involved in the regulation of extracellular matrix organization, cell cycle, ATM signaling and cellular senescence; and result in upregulation of expression of multiple extracellular matrix-related genes and proteins, down-regulation of immune/interferon-related genes and proteins, and increased sensitivity to apoptosis. Thus, in addition to classical ligand and tyrosine kinase-dependent (LYK-D) signaling, the IR regulates a second, ligand and tyrosine kinase-independent (LYK-I) pathway, which regulates the cellular machinery involved in senescence, matrix interaction and response to extrinsic challenges.
Keyphrases
- tyrosine kinase
- cell cycle
- extracellular matrix
- cell proliferation
- epidermal growth factor receptor
- type diabetes
- dna damage
- signaling pathway
- endothelial cells
- oxidative stress
- poor prognosis
- cell cycle arrest
- pi k akt
- endoplasmic reticulum stress
- glycemic control
- cell death
- protein kinase
- binding protein
- stress induced
- dendritic cells
- dna repair
- metabolic syndrome
- long non coding rna
- induced apoptosis
- dna damage response
- reactive oxygen species
- weight loss