Department of Pathology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA.
J Biol Chem. 2013 Jan 4;288(1):123-31. doi: 10.1074/jbc.M112.410910. Epub 2012 Oct 26.
Pseudopodium-enriched atypical kinase 1 (PEAK1) is a recently described tyrosine kinase that associates with the actin cytoskeleton and focal adhesion (FA) in migrating cells. PEAK1 is known to promote cell migration, but the responsible mechanisms remain unclear. Here, we show that PEAK1 controls FA assembly and disassembly in a dynamic pathway controlled by PEAK1 phosphorylation at Tyr-665. Knockdown of endogenous PEAK1 inhibits random cell migration. In PEAK1-deficient cells, FA lifetimes are decreased, FA assembly times are shortened, and FA disassembly times are extended. Phosphorylation of Tyr-665 in PEAK1 is essential for normal PEAK1 localization and its function in the regulation of FAs; however, constitutive phosphorylation of PEAK1 Tyr-665 is also disruptive of its function, indicating a requirement for precise spatiotemporal regulation of PEAK1. Src family kinases are required for normal PEAK1 localization and function. Finally, we provide evidence that PEAK1 promotes cancer cell invasion through Matrigel by a mechanism that requires dynamic regulation of Tyr-665 phosphorylation.
富含伪足的非典型激酶 1（PEAK1）是一种最近描述的酪氨酸激酶，它与迁移细胞中的肌动蛋白细胞骨架和黏着斑（FA）相关联。PEAK1 已知可促进细胞迁移，但负责的机制仍不清楚。在这里，我们表明 PEAK1 通过 Tyr-665 上的 PEAK1 磷酸化控制 FA 的组装和拆卸，这是一个由磷酸化控制的动态途径。内源性 PEAK1 的敲低会抑制随机细胞迁移。在 PEAK1 缺陷细胞中，FA 的寿命缩短，FA 的组装时间缩短，FA 的拆卸时间延长。PEAK1 中的 Tyr-665 磷酸化对于其在 FA 调节中的正常定位和功能是必需的；然而，PEAK1 Tyr-665 的组成性磷酸化也破坏了其功能，表明需要对 PEAK1 进行精确的时空调节。Src 家族激酶对于正常的 PEAK1 定位和功能是必需的。最后，我们提供了证据表明，PEAK1 通过依赖 Tyr-665 磷酸化的动态调节的机制促进了癌细胞穿过 Matrigel 的侵袭。
