Abstract 1983: Functional analysis of cancer-associated mutations in human LATS1 and LATS2 tumor suppressors.

Abstract

Abstract Large Tumor Suppressor LATS1 and LATS2 (LATS1/2) are the key kinases of the hippo pathway, which regulates organ size and tumorigenesis in Drosophila and mammals in an evolutionary conserved pattern. Lats1 deficient mice develop soft tissue sarcomas, while disruption of Lats2 in mice and lats(wts) in Drosophila cause embryonic lethality. The Cancer Genome Project has identified 31 Lats1 and 21 Lats2 somatic mutations in the primary tumor tissues from a variety of human cancers, such as lung and ovarian cancer. However, the consequences of these mutations are still to be elucidated. In our study, evolutionary conservation analysis and structure remodeling predict 9 potentially damaging missense mutations, seven of which are located in the kinase domain. Immunoblotting demonstrates that one of the LATS2 mutants does not encode the protein product, whereas the other LATS1/2 mutants impair their phosphorylation, and attenuate their kinase activities on phosphorylating oncogene YAP. Furthermore, luciferase-based reporter assay shows that transcriptional coactivator activity of YAP is inhibited by wild type LATS1/2, but not by the mutants. In addition, in vivo transgenic expressions of LATS1/2 mutants result in less growth suppression in the Drosophila wing, when compared with the wild type. LATS1/2 mutants also fail to fully rescue the lethality causing by endogenous lats(wts) knockdown. Together, these results suggest that human LATS1 and LATS2 mutations deregulate oncogene YAP and highlight the crucial role of hippo pathway control in tumor suppression. Citation Format: Tian Yu, John F. Bachman, Zhi-Chun Lai. Functional analysis of cancer-associated mutations in human LATS1 and LATS2 tumor suppressors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1983. doi:10.1158/1538-7445.AM2013-1983