Insulin acts through the insulin receptor (IR) tyrosine kinase and two major canonical post-receptor signaling pathways (the IRS-1/PI3K/Akt pathway and the Shc/Ras/MAP kinase pathway) to exert its classic metabolic and mitogenic actions. To create a detailed map of how different domains of the receptor might be linked to different insulin actions, we created cells in which endogenous IR and IGF1R had been genetically inactivated, after which the cells were reconstituted with either the wild-type IR, a kinase-dead mutant of IR (K1030R-IR) , a truncated IR lacking just the C-terminus of IR (∆CT-IR) and a truncated IR with the juxtamembrane domain only inside the cell (JMO-IR) . Using these cells and a multi-omics approach, we have uncovered a second novel IR signaling pathway that is dependent on the intracellular domain of IR but is ligand and tyrosinekinase-independent (LYK-I for short) . We find that the LYK-I actions of the IR are mediated by changes in a phosphorylation of a network of proteins involved in cell cycle/mitosis, ATM signaling, extracellular matrix organization, and cellular senescence. These actions result in upregulation of expression of multiple extracellular matrix-related genes and proteins, and down-regulation of immune/interferon-related and cellular senescence related genes and proteins. Functionally, LYK-I signaling results in increased cell proliferation and increased sensitivity to apoptosis. Thus, in addition to classical ligand and tyrosine kinase-dependent signaling, the IR regulates a second, novel ligand and tyrosine kinase-independent (LYK-I) pathway which regulates the cellular machinery involved in cellular senescence, extracellular matrix interaction and apoptotic sensitivity.


H.Nagao: None. W.Cai: None. H.Pan: n/a. T.M.Batista: None. B.Brandao: n/a. C.Kahn: Advisory Panel; Kaleido, Consultant; Cellarity, Flagship Pioneering, Sana Biotechnology Inc.

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