1. Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis.
- Author
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Nagao, Hirofumi, Jayavelu, Ashok Kumar, Cai, Weikang, Pan, Hui, Dreyfuss, Jonathan M., Batista, Thiago M., Brandão, Bruna B., Mann, Matthias, and Kahn, C. Ronald
- Subjects
CELL receptors ,INSULIN regulation ,INSULIN receptors ,CELL cycle regulation ,EXTRACELLULAR matrix ,CELLULAR aging ,PROTEIN-tyrosine kinases - Abstract
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. Nagao et al. show that the insulin receptor can mediate receptor-dependent, but ligand- and tyrosine kinase-independent, events. These are associated with regulation of extracellular matrix, cell cycle, ATM signaling, senescence and apoptosis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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