Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Nature Communications |
Volume | 14 |
Issue number | 1 |
Pages (from-to) | 57 |
ISSN | 2041-1723 |
DOIs | |
Publication status | Published - 4 Jan 2023 |
Externally published | Yes |
Bibliographical note
© 2023. The Author(s).
- Apoptosis/genetics, Cell Division/genetics, Insulin/metabolism, Ligands, Phosphorylation, Protein-Tyrosine Kinases/metabolism, Receptor, Insulin/genetics, Cellular Senescence/genetics, Humans, Animals, Mice
Research areas
ID: 346585564