Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin.
Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin.
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Invadopodium形成的分子机制：N-WASP-ARP2/3复合途径和Cofilin的作用。
DOI：
10.1083/jcb.200407076
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发表时间：
2005-01-31
影响因子：
7.8
通讯作者：
Condeelis, John
中科院分区：
文献类型：
--
作者：
Yamaguchi, Hideki;Lorenz, Mike;Kempiak, Stephan;Sarmiento, Corina;Coniglio, Salvatore;Symons, Marc;Segall, Jeffrey;Eddy, Robert;Miki, Hiroaki;Takenawa, Tadaomi;Condeelis, John
侵袭伪足是由侵袭性癌细胞形成的具有基质降解活性的富含肌动蛋白的膜突起。我们已经研究了在转移性癌细胞中侵袭足形成的分子机制。表皮生长因子（EGF）受体激酶抑制剂阻断invadopodium的形成在血清的存在下，EGF刺激血清饥饿的细胞诱导invadopodium的形成。RNA干扰和显性负突变体表达分析表明，神经WASP（N-WASP），Arp 2/3复合物，及其上游调控因子，Nck 1，Cdc 42，和Ncb，是必要的invadopodium形成。延时分析显示，侵入伪足是在细胞外围重新形成的，它们的寿命从几分钟到几小时不等。寿命短的入侵伪足是能动的，而寿命长的入侵伪足往往是静止的。有趣的是，通过RNA干扰抑制cofilin表达抑制了长寿命侵袭伪足的形成，导致仅形成具有较少基质降解活性的短寿命侵袭伪足。这些结果表明EGF受体信号通过N-WASP-Arp 2/3途径调节侵袭足的形成，并且cofilin对于侵袭足的稳定和成熟是必需的。
Invadopodia are actin-rich membrane protrusions with a matrix degradation activity formed by invasive cancer cells. We have studied the molecular mechanisms of invadopodium formation in metastatic carcinoma cells. Epidermal growth factor (EGF) receptor kinase inhibitors blocked invadopodium formation in the presence of serum, and EGF stimulation of serum-starved cells induced invadopodium formation. RNA interference and dominant-negative mutant expression analyses revealed that neural WASP (N-WASP), Arp2/3 complex, and their upstream regulators, Nck1, Cdc42, and WIP, are necessary for invadopodium formation. Time-lapse analysis revealed that invadopodia are formed de novo at the cell periphery and their lifetime varies from minutes to several hours. Invadopodia with short lifetimes are motile, whereas long-lived invadopodia tend to be stationary. Interestingly, suppression of cofilin expression by RNA interference inhibited the formation of long-lived invadopodia, resulting in formation of only short-lived invadopodia with less matrix degradation activity. These results indicate that EGF receptor signaling regulates invadopodium formation through the N-WASP–Arp2/3 pathway and cofilin is necessary for the stabilization and maturation of invadopodia.