Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Box 280, SE-17177 Stockholm, Sweden.
Biol Cell. 2010 Jan 14;102(4):215-30. doi: 10.1042/BC20090033.
The F-BAR {Fes/CIP4 [Cdc42 (cell division cycle 42)-interacting protein 4] homology and BAR (Bin/amphiphysin/Rvs)} proteins have emerged as important co-ordinators of signalling pathways that regulate actin assembly and membrane dynamics. The presence of the F-BAR domain is the hallmark of this family of proteins and the CIP4 (Cdc42-interacting protein 4) was one of the first identified vertebrate F-BAR proteins. There are three human CIP4 paralogues, namely CIP4, FBP17 (formin-binding protein 17) and Toca-1 (transducer of Cdc42-dependent actin assembly 1). The CIP4-like proteins have been implicated in Cdc42-dependent actin reorganization and in regulation of membrane deformation events visible as tubulation of lipid bilayers.
We performed side-by-side analyses of the three CIP4 paralogues. We found that the three CIP4-like proteins vary in their effectiveness to catalyse membrane tubulation and actin reorganization. Moreover, we show that the CIP4-dependent membrane tubulation is enhanced in the presence of activated Cdc42. Some F-BAR members have been shown to have a role in the endocytosis of the EGF (epidermal growth factor) receptor and this prompted us to study the involvement of the CIP4-like proteins in signalling of the PDGFRbeta [PDGF (platelet-derived growth factor) beta-receptor]. We found that knock-down of CIP4-like proteins resulted in a prolonged formation of PDGF-induced dorsal ruffles, as well as an increased PDGF-dependent cell migration. This was most likely a consequence of a sustained PDGFRbeta activation caused by delayed internalization of the receptor in the cells treated with siRNA (small interfering RNA) specific for the CIP4-like proteins.
Our findings show that CIP4-like proteins induced membrane tubulation downstream of Cdc42 and that they have important roles in PDGF-dependent actin reorganization and cell migration by regulating internalization and activity of the PDGFRbeta. Moreover, the results suggest an important role for the CIP4-like proteins in the regulation of the activity of the PDGFRbeta.
F-BAR {Fes/CIP4 [Cdc42（细胞分裂周期 42）相互作用蛋白 4]同源和 BAR（Bin/ amphiphysin/Rvs）} 蛋白已成为调节肌动蛋白组装和膜动力学的信号通路的重要协调因子。该蛋白家族的标志是存在 F-BAR 结构域，CIP4（Cdc42 相互作用蛋白 4）是最早鉴定的脊椎动物 F-BAR 蛋白之一。人类有三个 CIP4 同源物，即 CIP4、FBP17（formin 结合蛋白 17）和 Toca-1（Cdc42 依赖的肌动蛋白组装 1 的转导物）。CIP4 样蛋白已被牵连到 Cdc42 依赖的肌动蛋白重排以及调节脂质双层管状化等可见的膜变形事件中。
我们对三种 CIP4 同源物进行了并排分析。我们发现，三种 CIP4 样蛋白在催化膜管状化和肌动蛋白重排方面的效果不同。此外，我们表明，在存在激活的 Cdc42 的情况下，CIP4 依赖性的膜管状化会增强。一些 F-BAR 成员已被证明在 EGF（表皮生长因子）受体的内吞作用中有作用，这促使我们研究 CIP4 样蛋白在 PDGFRbeta [PDGF（血小板衍生生长因子）β受体]信号转导中的作用。我们发现，CIP4 样蛋白的敲低导致 PDGF 诱导的背侧皱襞形成时间延长，以及 PDGF 依赖性细胞迁移增加。这很可能是由于用针对 CIP4 样蛋白的 siRNA（小干扰 RNA）处理细胞后，受体内化延迟导致 PDGFRbeta 持续激活的结果。
我们的研究结果表明，CIP4 样蛋白在 Cdc42 下游诱导膜管状化，并且通过调节 PDGFRbeta 的内化和活性，在 PDGF 依赖性肌动蛋白重排和细胞迁移中具有重要作用。此外，结果表明 CIP4 样蛋白在调节 PDGFRbeta 活性方面具有重要作用。
