TAZ Protein Accumulation Is Negatively Regulated by YAP Abundance in Mammalian Cells

被引:63
作者
Finch-Edmondson, Megan L. [1 ,4 ,5 ]
Strauss, Robyn P. [2 ]
Passman, Adam M. [2 ]
Sudol, Marius [2 ,4 ,5 ,6 ]
Yeoh, George C. [1 ,2 ]
Callus, Bernard A. [1 ,3 ]
机构
[1] Univ Western Australia, Sch Chem & Biochem, Nedlands, WA 6009, Australia
[2] Harry Perkins Inst Med Res, Med Res Ctr, Nedlands, WA 6009, Australia
[3] Notre Dame Univ, Sch Hlth Sci, Fremantle, WA 6959, Australia
[4] Natl Univ Singapore, Dept Physiol, NUS Yong Loo Lin Sch Med, Singapore 117411, Singapore
[5] Natl Univ Singapore, Mechanobiol Inst MBI, Singapore 117411, Singapore
[6] ASTAR, IMCB, Singapore 138673, Singapore
关键词
YES-ASSOCIATED PROTEIN; TUMOR-SUPPRESSOR; INHIBITS APOPTOSIS; PROLIFERATION; DOMAIN; ACTIVATION; ONCOGENE; GROWTH; PHOSPHORYLATION; IDENTIFICATION;
D O I
10.1074/jbc.M115.692285
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mammalian Hippo signaling pathway regulates cell growth and survival and is frequently dysregulated in cancer. YAP and TAZ are transcriptional coactivators that function as effectors of this signaling pathway. Aberrant YAP and TAZ activity is reported in several human cancers, and normally the expression and nuclear localization of these proteins is tightly regulated. We sought to establish whether a direct relationship exists between YAP and TAZ. Using knockdown and overexpression experiments we show YAP inversely regulates the abundance of TAZ protein by proteasomal degradation. Interestingly this phenomenon was uni-directional since TAZ expression did not affect YAP abundance. Structure/function analyses suggest that YAP-induced TAZ degradation is a consequence of YAP-targeted gene transcription involving TEAD factors. Subsequent investigation of known regulators of TAZ degradation using specific inhibitors revealed a role for heat shock protein 90 and glycogen synthase kinase 3 but not casein kinase 1 nor LATS in YAP-mediated TAZ loss. Importantly, this phenomenon is conserved from mouse to human; however, interestingly, different YAP isoforms varied in their ability to degrade TAZ. Since shRNA-mediated TAZ depletion in HeLa and D645 cells caused apoptotic cell death, we propose that isoform-specific YAP-mediated TAZ degradation may contribute to the contradicting roles reported for YAP overexpression. This study identifies a novel mechanism of TAZ regulation by YAP, which has significant implications for our understanding of Hippo pathway regulation, YAP-isoform specific signaling, and the role of these proteins in cell proliferation, apoptosis, and tumorigenesis.
引用
收藏
页码:27928 / 27938
页数:11
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