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.

胰岛素通过胰岛素受体 (IR) 酪氨酸激酶发挥其经典的代谢和促有丝分裂作用。在这里，使用具有短或长 β 亚基缺失或激酶活性位点 (K1030R) 突变的受体，我们发现了第二个以前未被识别的 IR 信号通路，它是细胞内结构域依赖性的，但配体和t y松香激酶-i _独立（LYK-I）。IR 的这些 LYK-1 作用与参与调节细胞外基质组织、细胞周期、ATM 信号和细胞衰老的蛋白质网络的磷酸化变化有关；并导致多种细胞外基质相关基因和蛋白质的表达上调，免疫/干扰素相关基因和蛋白质的下调，以及对细胞凋亡的敏感性增加。因此，除了经典的配体和酪氨酸激酶依赖性 (LYK-D) 信号传导之外，IR 还调节第二个配体和酪氨酸激酶非依赖性 (LYK-I) 通路，该通路调节参与衰老、基质相互作用和应对外部挑战。