| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
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
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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
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