2000 Fiscal Year Final Research Report Summary
Mechanism of the Expression of Various Phenotypes in Multiple Endocrine Neoplasia Type 2
| Project/Area Number |
10671112
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Nagoya University |
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Principal Investigator |
IMAI Tsuneo School of Medicine, Nagoya University, Assistant Professor, 医学部, 講師 (80252245)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Masahide School of Medicine, Nagoya University, Professor, 医学部, 教授 (40183446)
FUNAHASHI Hiroomi School of Medicine, Nagoya University, Assistant Professor, 医学部, 講師 (50135357)
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| Project Period (FY) |
1998 – 2000
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| Keywords | ret proto-oncogene / MEN2A / MEN2B / Shc / PI3-K / Gab1 / GDNF / MAPK |
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| Research Abstract |
Germ line mutations in ret proto-oncogene result in human hereditary diseases including MEN2A and MEN2B.MEN2A mutations induced disulfide-linked dimerization of the RET whereas MEN2B mutations appear to activate RET without dimerization. Tyrosine 1062 in RET represents a binding site for Shc adaptor proteins and is crucial for both RAS/ MAPK and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways. In the present study, we characterized how these two pathways diverge from tyrosine 1062, using human neuroblastoma and primitive neuroectodermal tumor cell lines expressing RET at high levels. In response to GDNF stimulation, Shc bound to Gab1 and Grb2 adaptor proteins as well as RET, and Shc and Gab1 were highly phosphorylated on tyrosine. The complex formation consisting of Shc, Gab1 and Grb2 was almost abolished by replacement of tyrosine 1062 in RET with phenylalanine, Tyrosine-phosphorylated Gab1 was also associated with p85 subunit of PI3-K, resulting in PI3-K and AKT activation, whereas Shc-Grb2-SOS complex was responsible for the RAS/ERK signaling pathway. These results suggested that the RAS and PI3-K pathways activated by GDNF bifurcate mainly through Shc bound to tyrosine 1062 in RET.Furthermore, using luciferase reporter-gene assays, we found that the RAS/ERK and PI3-K signaling pathways are important for activation of CREB and NF-kappaB in GDNF-treated cells, respectively.
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[Publications] Hayashi H, Ichihara M, Iwashita T, Murakami H, Shimono Y, Kawai K, Kurokawa K, Murakumo Y, Imai T, Funahashi H, Nakao A, Takahashi M.: "Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell-lined derived neurotrophic factor."Oncogene. 19. 4469-4475 (2000)
Description
「研究成果報告書概要(欧文)」より
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