Research Papers:

USP21 regulates Hippo pathway activity by mediating MARK protein turnover

Hung Thanh Nguyen _, Jan-Michael Kugler, Anand C. Loya and Stephen M. Cohen

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Oncotarget. 2017; 8:64095-64105. https://doi.org/10.18632/oncotarget.19322

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Hung Thanh Nguyen1,*, Jan-Michael Kugler1,*, Anand C. Loya2 and Stephen M. Cohen1

1Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

2Department of Pathology, Rigshospitalet, Copenhagen, Denmark

*These authors have contributed equally to this work

Correspondance to:

Hung Thanh Nguyen, email: [email protected]

Keywords: Hippo pathway, MARK, LATS, YAP, ubiquitin

Received: May 04, 2017     Accepted: June 10, 2017     Published: July 18, 2017


The Hippo pathway, which acts to repress the activity of YAP and TAZ trancriptional co-activators, serve as a barrier for oncogenic transformation. Unlike other oncoproteins, YAP and TAZ are rarely activated by mutations or amplified in cancer. However, elevated YAP/TAZ activity is frequently observed in cancer and often correlates with worse survival. The activity and stability of Hippo pathway components, including YAP/TAZ, AMOT and LATS1/2, are regulated by ubiquitin-mediated protein degradation. Aberrant expression of ubiquitin ligase complexes that regulate the turnover of Hippo components and deubiquitylating enzymes that counteract these ubiquitin ligases have been implicated in human cancer. Here we identify the USP21 deubiquitylating enzyme as a novel regulator of Hippo pathway activity. We provide evidence that USP21 regulates YAP/TAZ activity by controlling the stability of MARK kinases, which promote Hippo signaling. Low expression of USP21 in early stage renal clear cell carcinoma suggests that USP21 may be a useful biomarker.

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