Abstract
The YAP and TAZ transcriptional coactivators promote oncogenic transformation. Elevated YAP/TAZ activity has been documented in human tumors. YAP and TAZ are negatively regulated by the Hippo tumor suppressor pathway. The activity and stability of several Hippo pathway components, including YAP/TAZ, is regulated by ubiquitin mediated protein turnover and several ubiquitin ligase complexes have been implicated in human cancer. However, little is known about the deubiquitylating enzymes that counteract these ubiquitin ligases in regulation of the Hippo pathway. Here we identify the DUB3 family deubiquitylating enzymes as regulators of Hippo pathway activity. We provide evidence that DUB3 proteins regulate YAP/TAZ activity by controlling the stability of the E3 ligase ITCH, the LATS kinases and the AMOT family proteins. As a novel Hippo pathway regulator, DUB3 has the potential to act a tumor suppressor by limiting YAP activity.
Highlights
Transcriptional co-activators Yes-Associated Protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ) mediate the activity of the Hippo signaling pathway in control of cell proliferation and in tumor progression [1]
We present evidence implicating the family of DUB3 deubiquitylating enzymes in control of Yap/TAZ activity
The DUB3 family of deubiquitylating enzymes was identified in a shRNA-based screen for regulators of YAP/TAZ activity [23]
Summary
Transcriptional co-activators Yes-Associated Protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ) mediate the activity of the Hippo signaling pathway in control of cell proliferation and in tumor progression [1]. DUB3 proteins act by regulating the stability of the E3 ubiquitin ligase ITCH, the Hippo pathway core kinases LATS1 and LATS2, as well as the family of AMOT proteins, which play a scaffolding role in DUB3-mediated regulation of YAP. DUB3 expression had a more limited effect on the growth of BJ cells expressing a mutant form of YAP (S127A/S397A) that is not regulated by LATS kinases (BJp53kd/p16kd/HRas/YAPS127A/S397A; Fig 1G).
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