Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells
Insulin receptor substrate-1/SHP-2 interaction, a phenotype-dependent switching machinery of insulin-like growth factor-I signaling in vascular smooth muscle cells
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DOI：
10.1074/jbc.m405100200
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发表时间：
2004-09-24
影响因子：
4.8
通讯作者：
Sobue, K
中科院分区：
文献类型：
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作者：
Hayashi, K;Shibata, K;Sobue, K
胰岛素样生长因子- i （IGF-I）在多种细胞类型的增殖和分化等相互排斥的过程中发挥作用。igf - 1是一种有效的去分化血管平滑肌细胞（VSMCs）的丝裂原和运动原。然而，在分化的VSMCs中，igf - 1仅用于维持分化表型。在这里，我们研究了由igf - 1触发的VSMC表型依赖的信号传导和生物学过程。在分化的VSMCs中，igf -1激活了胰岛素受体底物-1 （IRS-1）募集的蛋白酪氨酸磷酸酶SHP-2。激活的SHP-2随后使IRS-1 Tyr(P)-895去磷酸化，导致IRS-1/Grb2/Sos到ERK和p38 MAPK的通路被阻断。相反，这种负调控在去分化的VSMCs中是沉默的，其中IGF-I通过IRS-1/Grb2/Sos相互作用相关的Ras激活激活两个mapk，导致增殖和迁移。因此，我们目前的研究结果表明，IRS-1/SHP-2相互作用作为控制VSMC表型依赖的igf -i诱导的信号通路和生物学过程的开关，这一机制可能适用于其他细胞。
Insulin-like growth factor-I (IGF-I) plays a role in mutually exclusive processes such as proliferation and differentiation in a variety of cell types. IGF-I is a potent mitogen and motogen for dedifferentiated vascular smooth muscle cells (VSMCs) in vivo and in vitro. However, in differentiated VSMCs, IGF-I is only required for maintaining the differentiated phenotype. Here we investigated the VSMC phenotype-dependent signaling and biological processes triggered by IGF-I. In differentiated VSMCs, IGF-I activated a protein-tyrosine phosphatase, SHP-2, recruited by insulin receptor substrate-1 (IRS-1). The activated SHP-2 then dephosphorylated IRS-1 Tyr(P)-895, resulting in blockade of the pathways from IRS-1/Grb2/Sos to the ERK and p38 MAPK. Conversely, such negative regulation was silent in dedifferentiated VSMCs, where IGF-I activated both MAPKs via IRS-1/Grb2/Sos interaction-linked Ras activation, leading to proliferation and migration. Thus, our present results demonstrate that the IRS-1/SHP-2 interaction acts as a switch controlling VSMC phenotype-dependent IGF-I-induced signaling pathways and biological processes, and this mechanism is likely to be applicable to other cells.