Cdc42-Interacting Protein 4 Promotes Breast Cancer Cell Invasion and Formation of Invadopodia through Activation of N-WASp
Cdc42-Interacting Protein 4 Promotes Breast Cancer Cell Invasion and Formation of Invadopodia through Activation of N-WASp
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DOI：
10.1158/0008-5472.can-09-4149
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Corey, Seth J.
中科院分区：
文献类型：
--
作者：
Pichot, Christina S.;Arvanitis, Constadina;Corey, Seth J.
在转移的最早阶段，乳腺癌细胞必须重组细胞骨架以影响细胞形状变化并促进细胞侵袭和运动。这些事件需要细胞骨架调节剂Cdc 42和Rho，它们的效应物如N-WASp/WAVE，以及肌动蛋白聚合的直接诱导剂如Arp 2/3。很少有人考虑塑造细胞膜的分子。F-BAR蛋白质CIP 4、TOCA-1和FBP 17产生膜曲率，并作为活化Cdc 42和N-WASp的支架蛋白。我们发现，与弱侵袭性或非侵袭性乳腺癌细胞系相比，CIP 4的表达在侵袭性乳腺癌细胞系中增加，而TOCA-1或FBP 17的表达没有增加。内源性CIP 4定位于迁移细胞的前缘和侵入明胶的细胞中的侵入伪足。由于CIP 4作为Cdc 42、Src和N-WASp的支架蛋白，我们测试了CIP 4的缺失是否会导致N-WASp功能降低。CIP 4和N-WASp之间的相互作用是表皮生长因子响应性的，并且通过小干扰RNA沉默CIP 4导致在Src依赖性活化位点（Y256）的N-WASp的酪氨酸磷酸化降低。CIP 4沉默也损害了MDA-MB-231细胞的迁移和侵袭，并与侵袭伪足形成和明胶降解减少有关。这项研究提出了CIP 4在促进MDA-MB-231乳腺癌细胞迁移和侵袭中的新作用，并建立了F-BAR蛋白对癌细胞运动和侵袭的贡献。Cancer Res; 70（21）; 8347-56. (C)2010年AACR。
In the earliest stages of metastasis, breast cancer cells must reorganize the cytoskeleton to affect cell shape change and promote cell invasion and motility. These events require the cytoskeletal regulators Cdc42 and Rho, their effectors such as N-WASp/WAVE, and direct inducers of actin polymerization such as Arp2/3. Little consideration has been given to molecules that shape the cell membrane. The F-BAR proteins CIP4, TOCA-1, and FBP17 generate membrane curvature and act as scaffolding proteins for activated Cdc42 and N-WASp. We found that expression of CIP4, but not TOCA-1 or FBP17, was increased in invasive breast cancer cell lines in comparison with weakly or noninvasive breast cancer cell lines. Endogenous CIP4 localized to the leading edge of migrating cells and to invadopodia in cells invading gelatin. Because CIP4 serves as a scaffolding protein for Cdc42, Src, and N-WASp, we tested whether loss of CIP4 could result in decreased N-WASp function. Interaction between CIP4 and N-WASp was epidermal growth factor responsive, and CIP4 silencing by small interfering RNA caused decreased tyrosine phosphorylation of N-WASp at a Src-dependent activation site (Y256). CIP4 silencing also impaired the migration and invasion of MDA-MB-231 cells and was associated with decreased formation of invadopodia and gelatin degradation. This study presents a new role for CIP4 in the promotion of migration and invasion of MDA-MB-231 breast cancer cells and establishes the contribution of F-BAR proteins to cancer cell motility and invasion. Cancer Res; 70(21); 8347-56. (C) 2010 AACR.