Abstract LB-126: Negative regulation of the Hippo pathway by the E3 ubiquitin ligase ITCH promotes tumorigenicity

Abstract

Abstract The Hippo tumor suppressor pathway regulates cellular proliferation and survival, thus has profound effects on normal cell fate and tumorigenesis. WW domain-containing proteins regulate diverse biological processes through interaction with proline-tyrosine (PPxY) containing targets. Here, we showed that the E3 ligase ITCH regulates stability of LATS1, a key components of the Hippo pathway through protein-protein interaction of the PPxY motifs of LATS1 and the WW domains of ITCH by showing both endogenous and exogenous LATS1 and ITCH co-immunoprecipitation and that a double mutation in LATS1 PPxY motifs abrogates ITCH-LATS1 interaction. Wild type, but not mutant, ITCH catalyzed ubiquitination of LATS1 and stimulated its proteosomal degradation. Activation of the Hippo pathway, either by overexpressing MST2 or culturing cells at high density, induced ITCH and subsequent degradation of LATS1. Modulation of LATS1 levels via ITCH overexpression or Knockdown was associated with status of YAP phosphorylation, its subcellular localization and subsequently its transcription co-activation function. While ITCH knockdown induced epithelial-mesenchymal transition (EMT) phenotypes and tumorigenicity, ITCH overexpression induced these phenotypes. These findings provide evidence of a novel functional link between ITCH and Hippo pathway, underscoring a critical role for this association in tumorogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-126. doi:10.1158/1538-7445.AM2011-LB-126