Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis

Hirofumi Nagao, Ashok Kumar Jayavelu, Weikang Cai, Hui Pan, Jonathan M. Dreyfuss, Thiago M. Batista, Bruna B. Brandão, Matthias Mann and C. Ronald Kahn ()
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Hirofumi Nagao: Harvard Medical School
Ashok Kumar Jayavelu: Max Planck Institute of Biochemistry
Weikang Cai: Harvard Medical School
Hui Pan: Harvard Medical School
Jonathan M. Dreyfuss: Harvard Medical School
Thiago M. Batista: Harvard Medical School
Bruna B. Brandão: Harvard Medical School
Matthias Mann: Max Planck Institute of Biochemistry
C. Ronald Kahn: Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35693-5

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