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; C. Ronald Kahn

doi:10.1038/s41467-022-35693-5

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, C. Ronald Kahn

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English
Article number	57
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-35693-5
State	Published - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

This work was supported by NIH grants R01DK031036 (to C.R.K.) and the Joslin DRC grant (P30DK036836). H.N. was supported by a Sunstar Foundation postdoctoral fellowship and a JSPS Overseas Research Fellowship. W.C. was supported by NIH grants K01 DK120740 and P30 DK057521. A.K.J. and M.M. were supported by the Max Planck Society for the Advancement of Science and by the German Research Foundation (DFG/Gottfried Wilhelm Leibniz Prize).

Funders	Funder number
Gottfried Wilhelm Leibniz Universität Hannover
Sunstar Foundation
National Institutes of Health (NIH)	R01DK031036
California Department of Fish and Game
Michigan Diabetes Research Center	P30DK036836
Deutsche Forschungsgemeinschaft
Japan Society for the Promotion of Science	P30 DK057521, K01 DK120740
Fritz-Haber-Institut der Max-Planck-Gesellschaft

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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

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.",

author = "Hirofumi Nagao and Jayavelu, \{Ashok Kumar\} and Weikang Cai and Hui Pan and Dreyfuss, \{Jonathan M.\} and Batista, \{Thiago M.\} and Brand{\~a}o, \{Bruna B.\} and Matthias Mann and Kahn, \{C. Ronald\}",

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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

PY - 2023/12

Y1 - 2023/12

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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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