サイトカイン受容体組み合わされたシグナリング複合体の本質的なサイトプラズミック転位

Atsushi Matsuzawa¹, Ping-Hui Tseng, Sivakumar Vallabhapurapu

¹Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.

Science (New York, N.Y.)

|July 19, 2008

まとめ

サイトカインシグナル伝達には,受容体での複雑なアセンブリが含まれます. キナーゼの活性化には,この複合体が,TRAF3の分解後,シグナル伝達経路を分離して,サイトゾールに移動することが必要です.

科学分野:

免疫学免疫学とは
細胞生物学細胞生物学
分子シグナリング

背景:

サイトカインシグナル伝達は,多成分複合体内の受容体近接タンパク質キナーゼ活性化に依存しています.
腫瘍死滅因子受容体 (TNFR) 家族のメンバーであるCD40は,複合形成を通して信号を発信します.

研究の目的:

CD40誘発信号複合体の組み立てとキナーゼ活性化のメカニズムを解明する.
信号伝達における特定のアダプター分子とタンパク質の分解の役割を調査する.

主な方法:

リガンド結合への反応としてCD40信号複合体の形成を調査した.
相互作用するタンパク質を特定し,キナーゼ活性を評価するために,共免疫プレシピテーションとウエスタン・ブロッティングを使用しました.
TRAF3の分解がシグナリング複合体の局所化と下流キナーゼ活性化に与える影響を調査した.

主要な成果:

CD40は,TRAF2,TRAF3,Ubc13,c-IAP1/2,IKKgamma (NEMO),およびMEKK1と結合して複合体を形成する.
TRAF2,Ubc13およびIKKgammaは,複雑な組み立てとMEKK1/MAPKのカスケード活性化に不可欠である.
キナーゼの活性化は,シグナリング複合体のサイトゾールへの転位に依存し,c-IAP1/2-誘発のTRAF3分解によって媒介されます.

結論:

2段階のシグナル伝達メカニズムは,CD40媒介のサイトカインシグナル伝達を制御する.
このメカニズムは,受容体での初期複合組成に続き,細胞転位により,MAPKとIKKの信号伝達の空間的および時間的な分離を可能にします.
このモデルは,他の先天性免疫受容体シグナル伝達経路にも適用できるかもしれません.

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