Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
Originalsprog | Engelsk |
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Tidsskrift | Nature Communications |
Vol/bind | 14 |
Udgave nummer | 1 |
Sider (fra-til) | 57 |
ISSN | 2041-1723 |
DOI | |
Status | Udgivet - 4 jan. 2023 |
Eksternt udgivet | Ja |
Bibliografisk note
© 2023. The Author(s).
ID: 346585564