ERKによるTSC2のリン酸化と機能的不活性化は,結核性硬化症と癌の病原性に対する意味を持つ

Li Ma¹, Zhenbang Chen, Hediye Erdjument-Bromage

¹Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Cell

|April 27, 2005

まとめ

細胞外信号調節キナーゼ (Erk) は,リン酸化によってTSC2を無効化し,結核性硬化症複合体 (TSC) の腫瘍成長を促します. Erk Erkをブロックする

科学分野:

腫瘍学腫瘍学
分子生物学は分子生物学である.
遺伝学遺伝学とは

背景:

結核性硬化症複合体 (TSC) は,TSC1またはTSC2遺伝子の変異によって引き起こされる腫瘍形成によって特徴づけられる遺伝疾患です.
TSCにおける腫瘍発生は,必ずしもヘテロジゴス性の喪失 (LOH) を伴うわけではありません.
活性化された細胞外信号調節キナーゼ (Erk) は,LOHのないTSC病変で観察されています.

研究の目的:

TSC腫瘍発生におけるErkの役割を調査する.
ErkがTSC2機能とmTORシグナル伝達に影響を与えるメカニズムを解明する.

主な方法:

TSC2.2のエルク依存型リン酸化を調査する.
TSC1-TSC2複合体の解離を分析する.
TSC2リン酸化がmTOR信号伝達と細胞増殖に与える影響を評価する.
構成的なERK活性化によるTSC2+/-腫瘍細胞に非リン酸化性TSC2変異体を使用.

主要な成果:

エルクに依存したリン酸化は,TSC1-TSC2解離につながる.
リン酸化TSC2は,mTORシグナル伝達,細胞増殖,腫瘍性変異の阻害が低下している.
非リン酸化可能なTSC2変異体の発現は,in vivoで腫瘍形成を阻害したが,野生型TSC2はそうしなかった.

結論:

Ras/MAPK経路,特にErkは,TSC複合体の上流に作用する.
ErkはmTORシグナル伝達を調節し,TSC2のリン酸化と不活性化を通じてTSCの進行に貢献します.
ターゲティング・エルクは,TSCに対する治療戦略を提供することができる.

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