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Role of Angiomotin-like 2 mono-ubiquitination on YAP inhibition

Miju Kim1, Minchul Kim1, Seong-Jun Park2

  • 1National Creative Research Center for Cell Division and Differentiation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.

EMBO Reports
|November 25, 2015
PubMed

Insights

The deubiquitinase USP9X targets Angiomotin-like 2 (AMOTL2), a key regulator of the YAP oncoprotein. AMOTL2 ubiquitination is essential for inhibiting YAP activity and Hippo pathway signaling.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncogenesis

Background:

  • The Hippo pathway, involving LATS1/2 kinases and Angiomotin (AMOT) family proteins, regulates the YAP oncoprotein.
  • The precise molecular mechanisms by which these inhibitors function remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of USP9X in regulating AMOTL2 and its impact on YAP activity.
  • To investigate the ubiquitination status of AMOTL2 and its functional consequences.

Main Methods:

  • Genetic manipulation (knockdown and overexpression) of USP9X and AMOTL2.
  • Biochemical assays to identify protein interactions and ubiquitination sites.
  • Western blotting to assess protein phosphorylation and ubiquitination.
  • Cell culture studies to evaluate YAP transcriptional activity.

Main Results:

  • USP9X deubiquitinates Angiomotin-like 2 (AMOTL2), and AMOTL2 mono-ubiquitination is crucial for YAP inhibition.
  • USP9X knockdown enhances LATS-mediated YAP phosphorylation and reduces YAP transcriptional output.
  • AMOTL2 ubiquitination at K347 and K408 is essential for its YAP inhibitory function.
  • Ubiquitinated AMOTL2 interacts with the UBA domain of LATS kinase, which is vital for LATS function.

Conclusions:

  • USP9X acts as a deubiquitinase for AMOTL2, modulating Hippo pathway signaling.
  • AMOTL2 ubiquitination is a critical regulatory step for YAP inhibition and Hippo pathway activation.
  • These findings reveal a novel mechanism in the regulation of the core Hippo pathway components.
Keywords:
AMOTL2Hippo pathwayLATS‐YAPUSP9Xmono‐ubiquitination

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