Rahmat Muhammad Bakhait, Zhang Songjing, Koh Cheng-Gee
Interdisciplinary Graduate School, Nanyang Technological University, Singapore.
School of Biological Sciences, Nanyang Technological University, Singapore.
Oncotarget. 2019 Feb 19;10(15):1525-1538. doi: 10.18632/oncotarget.26689.
The Hippo pathway regulates cell proliferation, survival, apoptosis and differentiation. During carcinogenesis, members of the Hippo pathway are mutated to avoid anoikis and promote anchorage independent growth. Although many regulators of the Hippo pathway have been reported, negative regulators of the hippo kinases are not well studied. Through an interactome screen, we found that POPX2 phosphatase interacts with several of the Hippo pathway core kinases, including LATS1 which is the direct kinase regulating the transcription co-activators, YAP and TAZ. Phosphorylated YAP/TAZ are retained in the cytoplasm and prevented from translocation into the nucleus to activate transcription of target genes. We found that POPX2 could dephosphorylate LATS1 on Threonine-1079, leading to inactivation of LATS1 kinase. As a result, YAP/TAZ are not phosphorylated and are able to translocate into the nucleus to activate target genes involved in cell proliferation. Furthermore, POPX2 knock-out using CRISPR in the highly metastatic MDA-MB-231 breast cancer cells results in decreased cell proliferation and impairment of anchorage independent growth. We propose that POPX2 act as a suppressor of the Hippo pathway through LATS1 dephosphorylation and inactivation.
Hippo信号通路调控细胞增殖、存活、凋亡和分化。在肿瘤发生过程中，Hippo信号通路的成员发生突变，以避免失巢凋亡并促进不依赖锚定的生长。尽管已经报道了许多Hippo信号通路的调节因子，但对Hippo激酶的负调节因子研究较少。通过相互作用组筛选，我们发现POPX2磷酸酶与几种Hippo信号通路核心激酶相互作用，包括直接调节转录共激活因子YAP和TAZ的激酶LATS1。磷酸化的YAP/TAZ保留在细胞质中，阻止其转运到细胞核中以激活靶基因的转录。我们发现POPX2可以使LATS1的苏氨酸-1079去磷酸化，导致LATS1激酶失活。结果，YAP/TAZ不被磷酸化，并能够转运到细胞核中以激活参与细胞增殖的靶基因。此外，在高转移性MDA-MB-231乳腺癌细胞中使用CRISPR敲除POPX2会导致细胞增殖减少和不依赖锚定生长的受损。我们提出，POPX2通过使LATS1去磷酸化和失活而作为Hippo信号通路的抑制因子。
