POPX2 is a novel LATS phosphatase that regulates the Hippo pathway
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Muhammad Bakhait Rahmat1, Songjing Zhang2 and Cheng-Gee Koh2
1Interdisciplinary Graduate School, Nanyang Technological University, Singapore
2School of Biological Sciences, Nanyang Technological University, Singapore
Cheng-Gee Koh, email: [email protected]
Keywords: Hippo pathway; POPX2 phosphatase; LATS1 kinase; YAP/TAZ; anchorage-independent growth
Received: October 25, 2018 Accepted: February 09, 2019 Published: February 19, 2019
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.
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