The Large Tumour Suppressor 1 (LATS1) is a serine/threonine kinase and tumour suppressor found downregulated in many human tumour types. Our lab and others previously revealed that LATS1 plays critical regulatory roles in various cancer development events, including cell proliferation, cell migration and apoptosis. However, despite such biological importance, relatively little is known regarding to how LATS1 is regulated at the molecular level. Through a recent binidng screen, we identified a HECT class E3 ubiqitin ligase ITCH (or API4) as a novel binding partner of LATS1. Further mapping showed that this interaction is particularly mediated through the PPxY (P, proline; x, any amino acids; Y, tyrosine) motifs of LATS1 and the WW domains of ITCH. Significantly, we found that ectopic expression of ITCH readily promotes downregulation of LATS1 proteins in a dose dependent manner and that this effect requries an intact ligase activity of ITCH. Further experiments also revealed that ITCH can promote in vivo polyubiquitination and subsequent degradation of LATS1 through the 26S proteasome pathway. Consistent with these results, stable shRNA knockdown of endogenous ITCH also causes upregulation of endogenous LATS1 in the MDA-MB-231 breast cancer cells, suggesting ITCH is a direct regulator of LATS1's protein stability. Together, our study provided convincing evidences demonstrating ITCH as the first negative regulator of the LATS1 tumour suppressor. Further elucidation of the effect of ITCH on LATS1's tumour suppressive activity may therefore shed light on our understanding of their roles in cancer development and therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5097.