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

肌细胞分化中s和hansaiption调节的共同机制

• 批准号: 15590246
• 负责人: HAYASHI Ken'ichiro
• 金额: $ 2.37万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590246/
• 关键词: smooth muscle cell; skeletal muscle cell; phenotypic modulation; IGF-I; signal transduction; IRS-1; SHP-2; ERK; 骨格筋細胞分化; SHPS-1; PI3K; PKB(Akt); MAPK; Ras; Grb2-Sos

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

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-I对维持分化表型起着至关重要的作用，这取决于IGF-I诱导的PI3K/PKB（Akt）通路的激活。在本研究中，我们研究了igf - 1在VSMC表型依赖性生物学效应中的分子机制。在分化的VSMCs中，igf -1通过招募酪氨酸磷酸化的IRS-1激活蛋白酪氨酸磷酸酶SHP-2。激活的SHP-2随后使IRS-1 pTyr-895去磷酸化，导致IRS-1/Grb2-Sos/Ras到ERK和p38MAPK的通路被阻断。相反，这种负调控在去分化的VSMC中是沉默的，其中IGF-I激活了两个MAPKs，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表型依赖的IGF-I信号传导和生物学效应的开关。更重要的是，在骨骼肌细胞的成肌分化过程中，igf -i诱导的PI3K/PKB（Akt）通路的激活起着关键作用，而ERK通路则根据成肌细胞的不同类型表现出不同的作用。MEK （ERK激酶）抑制剂（PD98059）处理显著增强igf -i诱导的L6成肌细胞肌管形成。相比之下，在C2C12成肌细胞中，PD98059处理激活了骨骼肌分化分子标记的表达，但显著抑制了肌管的形成。在igf - i刺激的L6成肌细胞中，PI3Kp85、SHP-2和Grb2被招募到酪氨酸磷酸化的IRS-1上，导致PI3K/PKB（Akt）、SHP-2和ERK的激活；PI3K/PKB（Akt）和SHP-2的激活是连续的，而ERK的激活是短暂的。在C2C12成肌细胞中，PI3K/PKB（Akt）和SHP-2在igf - i触发的成肌分化过程中也被激活，但ERK的激活水平较L6成肌细胞弱。然而，PI3K/PKB（Akt）通路通过酪氨酸磷酸化的IRS-1被激活，在L6成肌细胞中，SHP-2被酪氨酸磷酸化的SHPS-1招募，而不是IRS-1。根据这些结果，我们得出结论，在平滑肌细胞和骨骼肌细胞中，PI3K/PKB（Akt）通路由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

项目成果

Takahashi M.: "Epiregulin as a major autocrine/paracrine factor released from the ERK- and p38MAPK-activated vascular smooth muscle cells"Circulation. 108. 2524-2529 (2003)

Takahashi M.：“上皮调节蛋白是 ERK 和 p38MAPK 激活的血管平滑肌细胞释放的主要自分泌/旁分泌因子”循环。

Epiregulin as a major autocrine/paracrine factor released from the ERK-and p38MAPK-activated vascular smooth muscle cells

上皮调节蛋白是 ERK 和 p38MAPK 激活的血管平滑肌细胞释放的主要自分泌/旁分泌因子

• 发表时间: 2003
• 期刊: Circulation 108
• 作者: Takahashi M.;et. al.
• 通讯作者: et. al.

Vascular Remodeling Induced by Naturally Occurring Unsaturated Lysophosphatidic Acid In Vivo

• DOI: 10.1161/01.cir.0000089374.35455.f3
• 发表时间: 2003-10
• 期刊: Circulation: Journal of the American Heart Association
• 作者: Kenji Yoshida;W. Nishida;Ken’ichiro Hayashi;Y. Ohkawa;Akira Ogawa;J. Aoki;H. Arai;K. Sobue

Yoshida K.: "Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acid in vivo"Circulation. 108. 1746-1752 (2003)

Yoshida K.：“体内天然存在的不饱和溶血磷脂酸诱导的血管重塑”循环。