Role of Cbl in signaling from receptor tyrosine kinases

• Project/Area Number: 11671088
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Kobe University
• Principal Investigator: OKABAYASHI Yoshinori Kobe University School of medicine assistant professor, 医学部, 助教授 (10233363)
• Project Period (FY): 1999 – 2000
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: Cbl / EGF receptor / PI3 kinase / Akt / MAP kinase / apoptosis / PI-3キナーゼ / apoptosis

Research Abstract

In the present study, I investigated the role of Cbl and Cbl- phosphoinisitide (PI) 3 kinase complex in signaling from receptor tyrosine kinases, especially epidermal growth factor (EGF) receptors. For this end, I constructed adenoviral vectors carrying wild-type and mutant Cbl in which the binding sites of 85-kDa regulatory subunit of PI3 kinase were disrupted. The major binding site for PI3 kinase within Cbl was tyrosine at 731, which represents Tyr-Xaa-Xaa-Met motif. When wild-type Cbl was overexpressed in Cos, A431, and A549 cells, EGF receptor autophosphorylation, MAP kinase activation, and Akt activation in response to EGF stimulation was markedly reduced. Inhibition by mutant Cbl was similar to that by wild-type Cbl. Cbl abolished the protective effect of EGF on UV-induced apoptosis in Cos and A431 cells. Thus, Cbl inhibits EGF receptor kinase and PI3 kinase associated with Cbl does not have major role in mitogenic signaling from EGF receptors.