Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot, 76100, Israel.
Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, 20742, USA.
Cell Death Dis. 2018 Sep 24;9(10):985. doi: 10.1038/s41419-018-1005-z.
The tumor suppressor Hippo pathway negatively regulates the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) to inhibit cell growth and control organ size, whereas activation of YAP and TAZ is implicated in tumorigenesis and cancer metastasis. Here, we report that the nonreceptor tyrosine kinase PYK2 positively regulates TAZ and YAP transcriptional activity in triple-negative breast cancer (TNBC). We found that inhibition of PYK2 expression or its kinase activity substantially affects the steady-state level of TAZ and markedly facilitates its proteasomal degradation. This effect was specific to PYK2 inhibition and was not obtained by inhibition of FAK. Destabilization of TAZ was associated with profound effect of PYK2 inhibition on cell growth at low-density concomitant with reduced expression of TAZ-target genes and induction of cell apoptosis. We further show that PYK2 enhances the tyrosine phosphorylation of both TAZ and LATS1/2 and concomitantly TAZ stability, and that PYK2 protein level correlates with the level of TAZ protein in primary breast tumors. Together these observations suggest that PYK2 is an important regulator of the Hippo pathway, and its tyrosine kinase activity has a striking effect on TAZ stabilization and activation in TNBC.
肿瘤抑制因子 Hippo 通路通过负调控转录共激活因子 Yes 相关蛋白（YAP）和 PDZ 结合基序转录共激活因子（TAZ）来抑制细胞生长和控制器官大小，而 YAP 和 TAZ 的激活与肿瘤发生和癌症转移有关。在这里，我们报告非受体酪氨酸激酶 PYK2 在三阴性乳腺癌（TNBC）中正向调节 TAZ 和 YAP 的转录活性。我们发现抑制 PYK2 的表达或其激酶活性显著影响 TAZ 的稳定状态，并显著促进其蛋白酶体降解。这种效应是 PYK2 抑制所特有的，而不是通过抑制 FAK 获得的。TAZ 的不稳定与 PYK2 抑制在低密度时对细胞生长的深刻影响有关，同时伴随着 TAZ 靶基因表达的降低和细胞凋亡的诱导。我们进一步表明，PYK2 增强了 TAZ 和 LATS1/2 的酪氨酸磷酸化，同时也增强了 TAZ 的稳定性，并且 PYK2 蛋白水平与原发性乳腺癌肿瘤中 TAZ 蛋白的水平相关。综上所述，这些观察结果表明 PYK2 是 Hippo 通路的一个重要调节因子，其酪氨酸激酶活性对 TNBC 中 TAZ 的稳定和激活有显著影响。
