肝細胞増殖因子受容体(c-Met)を介するシグナル伝達の分子機構

• Project/Area Number: 07273108
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: 喜多村 直実 (喜多村 直美) 東京工業大学, 生命理工学部, 教授 (80107424)
• Co-Investigator(Kenkyū-buntansha): 伝田 公紀 東京工業大学, 生命理工学部, 助手 (50212064) ; 蛯名 洋介 徳島大学, 酵素科学研究センター, 教授 (00112227) ; 清野 進 千葉大学, 医学部, 教授 (80236067) ; 松井 利充 神戸大学, 医学部, 講師 (10219371) ; 東山 繁樹 大阪大学, 医学部, 助手 (60202272) ; 大工原 恭 鹿児島大学, 歯学部, 教授 (40028733)
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥118,000,000 (Direct Cost: ¥118,000,000); Fiscal Year 1999: ¥8,000,000 (Direct Cost: ¥8,000,000); Fiscal Year 1998: ¥8,000,000 (Direct Cost: ¥8,000,000); Fiscal Year 1997: ¥34,000,000 (Direct Cost: ¥34,000,000); Fiscal Year 1996: ¥34,000,000 (Direct Cost: ¥34,000,000); Fiscal Year 1995: ¥34,000,000 (Direct Cost: ¥34,000,000)
• Keywords: 肝細胞増殖因子(HGF) / c-Met / がん細胞の増殖制御 / MAPキナーゼ / Hrs結合蛋白質 / SH3ドメイン / 脱ユビキチン化酵素 / 肝細胞増殖因子 / がん細胞の浸潤性 / Ras蛋白質 / 細胞増殖制御 / HGF / c-Met受容体 / ErbBリガンド / HEP受容体 / スルホニール尿素受容体 / インスリンシグナル伝達系 / ErbB3 / HB-EGF / ガストリン受容体 / ソマトスタチン / GLUT4のトランスロケーション / Gas6 / Sky / 細胞増殖抑制 / インスリン受容体 / c-kit受容体

Research Abstract

肝細胞増殖因子(HGF)受容体(c-Met)遺伝子は種々のがんの発生に関わると考えられており、最近家族性腎がんの原因遺伝子として同定された。本研究ではc-Metを介する細胞内シグナル伝達機構について解析を行い以下の結果を得た。
(1)HGFは正常肝細胞の増殖を促進するが、多くの肝がん由来細胞に対してはむしろ増殖を抑制する。そこでHGFに対してc-Metを介して増殖抑制応答を示す肝がん由来HepG2細胞を用いてシグナル伝達機構を解析した。HGF刺激したHepG2細胞ではMAPキナーゼの活性化が強く促進された。MAPキナーゼ・キナーゼ(MEK)に対する特異的阻害剤の効果を調べたところ、低いレベルのMAPキナーゼの活性化を示す低濃度の阻害剤処理により、HGF刺激に対する細胞増殖抑制応答が阻害され増殖が促進した。一方MAPキナーゼの活性化を完全に阻害する高濃度の阻害剤処理では増殖が抑制された。以上の結果より、HGF刺激による細胞増殖の制御にはMAPキナーゼ経路が重要な役割を果たしているが、この経路が強く活性化されると増殖が抑制されることが示唆された。
(2)HrsはHGFで刺激された細胞においてc-Metを介して速やかにチロシンリン酸化される蛋白質である。またHrs結合蛋白質(Hbp)は、酵母two-hybrid法により単離された新しい蛋白質であり、構造内にSH3ドメインを持っている。このSH3ドメインに結合する蛋白質として脱ユビキチン化酵素UBPYが単離されている。そこでこのUBPYの機能を明らかにするために、HbpSH3ドメイン結合部位を欠損するUBPYを細胞に導入し解析した。その結果、結合部位を欠損するUBPYは増殖因子の細胞内分解を抑制することが明らかになった。したがってUBPYはHbpのSH3ドメインに結合し、増殖因子および受容体の分解経路に重要な役割を担っているものと考えられる。

Research Products

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