Common mechanism in the regulation of s and hansaiption in muscle cell differentiation

IGF-I是一种有效的促有丝分裂剂和运动原，在体内和体外的去分化的血管平滑肌细胞（VSMCs）。然而，在分化的VSMCs中，IGF-I对维持分化表型起着至关重要的作用，这依赖于IGF-I诱导的PI 3 K/PKB（Akt）通路的激活。在这项研究中，我们研究了IGF-I的VSMC表型依赖性生物学效应的分子机制。在分化的VSMC中，IGF-I通过募集酪氨酸磷酸化的IRS-1激活蛋白酪氨酸磷酸酶SHP-2。激活的SHP-2使IRS-1 pTyr-895去磷酸化，阻断IRS-1/Grb 2-Sos/Ras通路至ERK和p38 MAPK通路。相反，这种负调控在去分化的VSMC中是沉默的，其中IGF-I激活两种MAPK，导致VSMC增殖和迁移。因此，这些结果表明IRS-1/SHP-2相互作用作为控制VSMC表型依赖性IGF-I信号传导和生物学效应的开关。Alt ...更多信息 在骨骼肌细胞的肌源性分化过程中，IGF-I诱导的PI 3 K/PKB（Akt）通路的激活起着关键作用，而ERK通路的作用则因成肌细胞的细胞类型而异。MEK（ERK激酶）抑制剂（PD 98059）处理显著增强IGF-I诱导的L 6成肌细胞的肌管形成。相比之下，在C2 C12成肌细胞中，PD 98059处理激活了骨骼肌分化的分子标记物的表达，但显著抑制了肌管形成。在IGF-I刺激的L 6成肌细胞中，PI 3 Kp 85、SHP-2和Grb 2被募集到酪氨酸磷酸化的IRS-1，导致PI 3 K/PKB（Akt）、SHP-2和ERK的激活; PI 3 K/PKB（Akt）和SHP-2的激活是连续的，而ERK的激活是短暂的。在C2 C12成肌细胞中，PI 3 K/PKB（Akt）和SHP-2在IGF-I诱导的成肌分化过程中也被激活，但ERK的激活水平较L 6成肌细胞弱。然而，PI 3 K/PKB（Akt）通路通过酪氨酸磷酸化的IRS-1激活，如在L 6成肌细胞中，SHP-2被募集到酪氨酸磷酸化的SHPS-1而不是IRS-1。从这些结果中，我们得出结论，在平滑肌和骨骼肌细胞中，PI 3 K/PKB（Akt）通路被IGF-I受体介导的相同信号通路激活，但IGF-I对SHP-2的激活依赖于细胞类型特异性通路。少

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 plays a vital role for maintaining the differentiated phenotype, which depends on IGF-I-induced activation of PI3K/PKB(Akt) pathway. In this study, we investigated the molecular mechanism underlying VSMC phenotype-dependent biological effects of IGF-I. In differentiated VSMCs, IGF-I activated a protein tyrosine phosphatase, SHP-2, by recruiting to tyrosine-phosphorylated IRS-1. The activated SHP-2 then dephosphorylated IRS-1 pTyr-895, resulting in blockade of the pathways from IRS-1/Grb2-Sos/Ras to the ERK and p38MAPK. Conversely, such negative regulation was silent in dedifferentiated VSMCs, where IGF-I activated both MAPKs, leading to VSMC proliferation and migration. Thus, these results demonstrate that the IRS-1/SHP-2 interaction acts as a switch controlling VSMC phenotype-dependent IGF-I signalings and biological effects. Alt … More hough, in myogenic differentiation of skeletal muscle cells, IGF-I-induced activation of PI3K/PKB(Akt) pathway plays a critical role, the ERK pathway shows contrast effects depending on cell types of myoblast. Treatment of MEK (ERK kinase) inhibitor (PD98059) markedly enhanced IGF-I-induced myotube formation of L6 myoblasts. By contrast, in C2C12 myoblasts, treatment of PD98059 activated the expression of molecular markers for skeletal muscle differentiation, but significantly suppressed myotube formation. In IGF-I-stimulated L6 myoblasts, PI3Kp85, SHP-2, and Grb2 were recruited to tyrosine-phosphorylated IRS-1, resulting in activation of PI3K/PKB(Akt), SHP-2, and ERK ; the activation of PI3K/PKB(Akt) and SHP-2 was continuous, whereas the ERK activation was transient. In C2C12 myoblasts, PI3K/PKB(Akt) and SHP-2 were also activated during IGF-I-triggered myogenic differentiation, but the activation level of ERK was weak compared with that in L6 myoblasts. However, the PI3K/PKB(Akt) pathway was activated via tyrosine-phosphorylated IRS-1 as in L6 myoblasts, SHP-2 was recruited to tyrosine-phosphorylated SHPS-1 but not to IRS-1. From these results, we concluded that in smooth and skeletal muscle cells the PI3K/PKB(Akt) pathway is activated by the same signaling pathway mediated through IGF-I receptor but the activation of SHP-2 by IGF-I depends on cell-type specific pathways. Less