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  current news   Press   selected story    
     
  14th February 2011  
 

Hippo pathway-independent restriction of TAZ and YAP by angiomotin.

 
 




Authors
Siew Wee Chan1, Chun Jye Lim1, Yaan Fun Chong1, Ajaybabu Venkatesan Pobbati1, Caixia Huang1 and Wanjin Hong1,2.

1 - Cancer and Developmental Cell Biology Division, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673.
2 - Department of Biochemistry, National University of Singapore.

Published in J. Biol. Chem., 11th January 2011. [Epub ahead of print]

Abstract
The Hippo pathway restricts the activity of transcriptional coactivators TAZ and YAP by phosphorylating them for cytoplasmic sequestration or degradation. In this report, we describe an independent mechanism for the cell to restrict the activity of TAZ and YAP through interaction with angiomotin (Amot) and angiomotin-like 1 (AmotL1). Amot and AmotL1 were robustly co-immunoprecipitated with Flag-tagged TAZ and their interaction is dependent on the WW domain of TAZ and the PPXY motif in the N-terminus of Amot. Amot and AmotL1 also interact with YAP via the first WW domain of YAP. Overexpression of Amot and AmotL1 caused cytoplasmic retention of TAZ and suppressed its transcriptional outcome such as the expression of CTGF and Cyr61. Hippo refractory TAZ mutant (S89A) is also negatively regulated by Amot and AmotL1. HEK293 cells express the highest level of Amot and AmotL1 among 9 cell lines examined and silencing the expression of endogenous Amot increased the expression of CTGF and Cyr61 either at basal or upon overexpression of exogenous S89A. These results reveal a novel mechanism to restrict the activity of TAZ and YAP through physical interaction with Amot and AmotL1.

 
 

 
 


Figure Legend: A working model for diverse regulatory mechanisms for TAZ and YAP.
The Hippo pathway causes cytoplasmic sequestration of TAZ and YAP through phosphorylation of S89 and S127, respectively. Furthermore, Hippo pathway-mediated phosphorylation of S314 and S381 leads to further phosphorylation, ubiquitination and proteosomal degradation of TAZ and YAP, respectively. Interaction with TEADs is important for nuclear accumulation and transcriptional outcome of TAZ and YAP. The results presented in this study suggest that Amot and AmotL1 (likely also AmotL2) function as a negative regulator of TAZ and YAP through direct interaction with the WW domain of TAZ and the first WW domain of YAP via the first PPXY motif of Amot and AmotL1 that is also conserved in AmotL2, leading to their cytoplasmic retention.

For more information on Wanjin HONG’s laboratory, please click here.