Department of Pathology, Moores Cancer Center, University of California, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10920-5. doi: 10.1073/pnas.0914776107. Epub 2010 Jun 1.
Regulation of the actin-myosin cytoskeleton plays a central role in cell migration and cancer progression. Here, we report the discovery of a cytoskeleton-associated kinase, pseudopodium-enriched atypical kinase 1 (PEAK1). PEAK1 is a 190-kDa nonreceptor tyrosine kinase that localizes to actin filaments and focal adhesions. PEAK1 undergoes Src-induced tyrosine phosphorylation, regulates the p130Cas-Crk-paxillin and Erk signaling pathways, and operates downstream of integrin and epidermal growth factor receptors (EGFR) to control cell spreading, migration, and proliferation. Perturbation of PEAK1 levels in cancer cells alters anchorage-independent growth and tumor progression in mice. Notably, primary and metastatic samples from colon cancer patients display amplified PEAK1 levels in 81% of the cases. Our findings indicate that PEAK1 is an important cytoskeletal regulatory kinase and possible target for anticancer therapy.
细胞骨架肌动球蛋白的调节在细胞迁移和癌症进展中起着核心作用。在这里，我们报告了一种细胞骨架相关激酶——假足丰富的非典型激酶 1（PEAK1）的发现。PEAK1 是一种 190kDa 的非受体酪氨酸激酶，定位于肌动蛋白丝和黏着斑。PEAK1 发生Src 诱导的酪氨酸磷酸化，调节 p130Cas-Crk-paxillin 和 Erk 信号通路，并作为整合素和表皮生长因子受体（EGFR）的下游因子发挥作用，以控制细胞铺展、迁移和增殖。在癌细胞中扰乱 PEAK1 水平会改变其在小鼠中的无锚定生长和肿瘤进展。值得注意的是，81%的结肠癌患者的原发和转移样本中 PEAK1 水平升高。我们的研究结果表明，PEAK1 是一种重要的细胞骨架调节激酶，可能是抗癌治疗的靶点。
