Tyrosine phosphorylation of cortactin by the FAK-Src complex at focal adhesions regulates cell motility.
Tyrosine phosphorylation of cortactin by the FAK-Src complex at focal adhesions regulates cell motility.
复制标题
粘着斑处的 FAK-Src 复合物对 Cortactin 进行酪氨酸磷酸化，调节细胞运动。
DOI：
10.1186/1471-2121-12-49
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发表时间：
2011-11-13
期刊：
影响因子：
--
通讯作者：
Liao K
中科院分区：
文献类型：
--
作者：
Wang W;Liu Y;Liao K
细胞迁移在许多生理和病理过程中起重要作用，包括免疫细胞趋化和肿瘤转移。这是一个协调的过程，涉及肌动蛋白细胞骨架的动态变化及其与局部粘连的相互作用。在迁移细胞的前缘，肌动蛋白的重新排列及其与粘着斑的附着产生了运动所需的驱动力。然而，肌动蛋白丝附着在粘连灶上的机制仍不完全清楚。FAK-Src复合物的信号传导在调节肌动蛋白丝所附着的粘着斑处蛋白复合物的形成中起着至关重要的作用。Cordyn是一种F-肌动蛋白相关蛋白，也是Src激酶的底物，它通过SH3结构域和FAK的C-末端富含脯氨酸的区域与FAK相互作用。我们发现FAK中Tyr397的自磷酸化是FAK活化所必需的，但与coronin的相互作用并不需要，而是相关coronin的酪氨酸磷酸化所必需的。在局灶性粘连，coronin被磷酸化的酪氨酸残基已知被磷酸化的Src。酪氨酸磷酸化的coronin和它的能力，与肌动蛋白细胞骨架的调节细胞运动所需的串联。细胞运动性可以通过截短Core-rin的N-末端F-肌动蛋白结合结构域或通过阻断酪氨酸磷酸化（Y421/466/475/482F突变）来抑制。此外，突变型coronin磷酸化模拟物（Y421/466/475/482 E）与FAK相互作用的能力降低，并促进细胞运动。通过截短其N-末端F-肌动蛋白结合结构域，也可以抑制由corneum蛋白磷酸化模拟物对细胞运动的促进。我们的研究结果表明，corneum作为一个桥接分子之间的肌动蛋白丝和局灶性粘连。Coreplatin N-末端与F-肌动蛋白相关，而其C-末端与粘着斑相互作用。FAK-Src复合物对coronin的酪氨酸磷酸化调节其与FAK的相互作用，并增加其在粘着斑的周转，以促进细胞运动。
Cell migration plays an important role in many physiological and pathological processes, including immune cell chemotaxis and cancer metastasis. It is a coordinated process that involves dynamic changes in the actin cytoskeleton and its interplay with focal adhesions. At the leading edge of a migrating cell, it is the re-arrangement of actin and its attachment to focal adhesions that generates the driving force necessary for movement. However, the mechanisms involved in the attachment of actin filaments to focal adhesions are still not fully understood. Signaling by the FAK-Src complex plays a crucial role in regulating the formation of protein complexes at focal adhesions to which the actin filaments are attached. Cortactin, an F-actin associated protein and a substrate of Src kinase, was found to interact with FAK through its SH3 domain and the C-terminal proline-rich regions of FAK. We found that the autophosphorylation of Tyr397 in FAK, which is necessary for FAK activation, was not required for the interaction with cortactin, but was essential for the tyrosine phosphorylation of the associated cortactin. At focal adhesions, cortactin was phosphorylated at tyrosine residues known to be phosphorylated by Src. The tyrosine phosphorylation of cortactin and its ability to associate with the actin cytoskeleton were required in tandem for the regulation of cell motility. Cell motility could be inhibited by truncating the N-terminal F-actin binding domains of cortactin or by blocking tyrosine phosphorylation (Y421/466/475/482F mutation). In addition, the mutant cortactin phosphorylation mimic (Y421/466/475/482E) had a reduced ability to interact with FAK and promoted cell motility. The promotion of cell motility by the cortactin phosphorylation mimic could also be inhibited by truncating its N-terminal F-actin binding domains. Our results suggest that cortactin acts as a bridging molecule between actin filaments and focal adhesions. The cortactin N-terminus associates with F-actin, while its C-terminus interacts with focal adhesions. The tyrosine phosphorylation of cortactin by the FAK-Src complex modulates its interaction with FAK and increases its turnover at focal adhesions to promote cell motility.
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