Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis
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Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis. / Nagao, Hirofumi; Jayavelu, Ashok Kumar; Cai, Weikang; Pan, Hui; Dreyfuss, Jonathan M; Batista, Thiago M; Brandão, Bruna B; Mann, Matthias; Kahn, C Ronald.
I: Nature Communications, Bind 14, Nr. 1, 04.01.2023, s. 57.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis
AU - Nagao, Hirofumi
AU - Jayavelu, Ashok Kumar
AU - Cai, Weikang
AU - Pan, Hui
AU - Dreyfuss, Jonathan M
AU - Batista, Thiago M
AU - Brandão, Bruna B
AU - Mann, Matthias
AU - Kahn, C Ronald
N1 - © 2023. The Author(s).
PY - 2023/1/4
Y1 - 2023/1/4
N2 - 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.
AB - 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.
KW - Apoptosis/genetics
KW - Cell Division/genetics
KW - Insulin/metabolism
KW - Ligands
KW - Phosphorylation
KW - Protein-Tyrosine Kinases/metabolism
KW - Receptor, Insulin/genetics
KW - Cellular Senescence/genetics
KW - Humans
KW - Animals
KW - Mice
U2 - 10.1038/s41467-022-35693-5
DO - 10.1038/s41467-022-35693-5
M3 - Journal article
C2 - 36599833
VL - 14
SP - 57
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
ER -
ID: 346585564