PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility.
PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility.
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DOI：
10.1083/jcb.200708194
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发表时间：
2008-01-14
期刊：
影响因子：
--
通讯作者：
Schlaepfer DD
中科院分区：
文献类型：
--
作者：
Lim Y;Lim ST;Tomar A;Gardel M;Bernard-Trifilo JA;Chen XL;Uryu SA;Canete-Soler R;Zhai J;Lin H;Schlaepfer WW;Nalbant P;Bokoch G;Ilic D;Waterman-Storer C;Schlaepfer DD
整合素与基质蛋白如纤连蛋白（FN）结合导致形成调节迁移的粘着斑（FA）细胞接触位点。RhoA GTP酶促进FA的形成，但FA相关的RhoA特异性鸟嘌呤核苷酸交换因子（GEFs）仍然未知。在这里，我们表明，富含脯氨酸的激酶-2（Pyk 2）的水平增加后，在小鼠胚胎成纤维细胞（MEFs）的粘着斑激酶（FAK）的损失。此外，我们证明Pyk 2通过促进p190 RhoGEF表达促进RhoA激活，FA形成升高和细胞增殖增强。在正常MEFs中，p190 RhoGEF敲低抑制FN相关的RhoA激活、FA形成和细胞迁移。p190 RhoGEF相关GEFH 1的敲低不影响FAK−/−或正常MEFs中FA的形成。p190 RhoGEF过表达增强依赖于FAK结合的MEFs中RhoA活化和FA形成，并与p190 RhoGEF FA募集和酪氨酸磷酸化相关。这些研究阐明了Pyk 2对FAK损失的补偿功能，并确定FAK-p190 RhoGEF复合物是FN刺激细胞运动过程中FA形成的重要整合素近端调节因子。
Integrin binding to matrix proteins such as fibronectin (FN) leads to formation of focal adhesion (FA) cellular contact sites that regulate migration. RhoA GTPases facilitate FA formation, yet FA-associated RhoA-specific guanine nucleotide exchange factors (GEFs) remain unknown. Here, we show that proline-rich kinase-2 (Pyk2) levels increase upon loss of focal adhesion kinase (FAK) in mouse embryonic fibroblasts (MEFs). Additionally, we demonstrate that Pyk2 facilitates deregulated RhoA activation, elevated FA formation, and enhanced cell proliferation by promoting p190RhoGEF expression. In normal MEFs, p190RhoGEF knockdown inhibits FN-associated RhoA activation, FA formation, and cell migration. Knockdown of p190RhoGEF-related GEFH1 does not affect FA formation in FAK−/− or normal MEFs. p190RhoGEF overexpression enhances RhoA activation and FA formation in MEFs dependent on FAK binding and associated with p190RhoGEF FA recruitment and tyrosine phosphorylation. These studies elucidate a compensatory function for Pyk2 upon FAK loss and identify the FAK–p190RhoGEF complex as an important integrin-proximal regulator of FA formation during FN-stimulated cell motility.
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