Dynamic reorganization of cytoskeletion by WASP family proteins

WASP 家族蛋白对细胞骨架的动态重组

• 批准号: 12307003
• 负责人: TAKENAWA Tadaomi
• 金额: $ 26万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12307003/
• 关键词: actin; cell movement; WASP; WAVE; cytoskeleton; 神経突起; N-WASP; チロシンキナーゼ; ユビキチン化

It is already well known that a variety of cells rearrange cytoskeleton, prepare for cell division, and stimulate motility and migration in response to various stimuli. The directed migration of cells is one of fundamental phenomena of life, including migration toward inflammatory sites, and invasion and metastasis of cancer cells.We found WASP and WAVE proteins which are related to cytoskeleton reorganization and cell migration. All these proteins have VCA regions at C-terminal area in which V region binds actin and CA region binds Arp2/3 complex. As a result, these proteins nucleate actin filaments and enhance actin polymerization. On the other hand, at N-terminal area, there are regions to which regulatory molecules bind. N-WASP binds several molecules such as WIP, WISH, Cdc42 and PIP2, and WAVE binds IRSp53, followed by the exposure of VCA region of these proteins. Consequently, these proteins bind to Arp2/3 complex and polymerize actin filaments. Finally, N-WASP which is located downstream of Cdc42 induces filopodia formation. WAVE which is located downstream of Rac induces lamellipodia formation. These proteins are present at the leading edge of moving cells and generate driving force.

众所周知，各种细胞会重新排列细胞骨架，为细胞分裂做准备，并刺激运动和迁移以响应各种刺激。细胞的定向迁移是生命的基本现象之一，包括向炎症部位的迁移、癌细胞的侵袭和转移，我们发现了与细胞骨架重组和细胞迁移相关的WASP和WAVE蛋白。所有这些蛋白质的C端都有VCA区，其中V区与肌动蛋白结合，CA区与Arp 2/3复合物结合。因此，这些蛋白质使肌动蛋白丝成核并增强肌动蛋白聚合。另一方面，在N-末端区域，存在调节分子结合的区域。N-WASP结合几种分子，如WISH，Cdc 42和PIP 2，WAVE结合IRSp 53，然后暴露这些蛋白的VCA区域。因此，这些蛋白质结合Arp 2/3复合物和肌动蛋白丝。最后，位于Cdc 42下游的N-WASP诱导丝状伪足形成。位于Rac下游的WAVE诱导板状伪足形成。这些蛋白质存在于运动细胞的前沿并产生驱动力。

项目成果

Yamaguchi, H., Miki, H., Takenawa, T: "Neural Wiskott-Aldrich Syndrome Protein is involved in hepatocyte growth factor-induced migration, invasion, and tuboligenesis of epithelial cells"Cancer Res.. 62. 2503-2509 (2002)

Yamaguchi, H.、Miki, H.、Takenawa, T：“神经 Wiskott-Aldrich 综合征蛋白参与肝细胞生长因子诱导的上皮细胞迁移、侵袭和小管生成”Cancer Res.. 62. 2503-2509 (2002

Otsuki, M., Itoh, T., Takenawa, T.: "N-WASP is recruited to rafts and associates with wndophilin A in response to EGF"J. Biol. Chem.. 278. 6461-6469 (2003)

Otsuki, M., Itoh, T., Takenawa, T.：“N-WASP 被募集到筏上并与亲细胞蛋白 A 结合以响应 EGF”J。

Suetsugu,S., Hattori,M., Miki,H., Tezuka,T., Yamamoto,T., Mkoshima,K., Takenawa,T.: "Sustained Activation of N-WASP through Phosphorylation Is Essential for Neurite Extension"Dev.Cell. 3. 645-658 (2002)

Suetsugu,S.、Hattori,M.、Miki,H.、Tezuka,T.、Yamamoto,T.、Mkoshima,K.、Takenawa,T.：“通过磷酸化持续激活 N-WASP 对于神经突延伸至关重要”

Suetsugu, S: "Requirement of the basic region of N-WASP/WAVE2 for actin-based motility"Biochem. Biophys. Res. Commun. 282. 739-744 (2001)

Suetsugu, S：“N-WASP/WAVE2 基本区域对于基于肌动蛋白的运动的要求”Biochem。

Ijuin, T., Takenawa, T.: "SKIP Negatively Regulates Insulin-Induced GLUT4 Translocation and Membrane Ruffle Formation"Mol Cell Biol.. 23. 1209-1220 (2003)

Ijuin, T., Takenawa, T.：“SKIP 负向调节胰岛素诱导的 GLUT4 易位和膜皱褶形成”Mol Cell Biol.. 23. 1209-1220 (2003)