Understanding the Hippo-LATS pathway in tumorigenesis
Grieve, Stacy Leanne
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The Hippo-LATS signaling pathway originally identified in Drosophila is conserved in mammalian systems and serves essential roles in mediating size control as well as tumorigenesis. In humans, the core kinase cassette consisting of adaptor proteins WW45 and MOB1, and Ser/Thr kinases MST1/2 and LATS1/2 signal by phosphorylating and inactivating transcriptional co-activators YAP and TAZ, causing cell growth arrest. As the central kinases within the Hippo-LATS pathway, examining the cellular and molecular phenotypes of LATS1 and LATS2 (LATS) will provide insight into the role of this pathway in tumorigenesis. By simultaneously knocking down both LATS1 and LATS2, genes that were differentially expressed were identified through a whole human genome microarray screen. The multitude of genes identified including CYR61, MYLK, CDKN1A, SLIT2, and TP53INP1 not only provide further evidence for the role of LATS in cell proliferation and apoptosis, but also implicate LATS in novel functions such as cell motility. Loss of LATS1 and/or LATS2 enhances cell migration whereas overexpression of LATS1 dramatically inhibits cell migration in multiple cell lines. The ability of LATS to regulate cell migration occurs through two potential mechanisms. Firstly, LATS functions through its kinase substrates YAP and/or TAZ, or alternatively, LATS1 directly binds actin and inhibits actin polyermization. Thus, through loss of functions studies, we identified a novel role for LATS in regulating cell migration as well as novel mechanisms of LATS function. As an important signaling molecule within the cell, LATS and the Hippo-LATS pathway are tightly regulated. Using clues from the Drosophila pathway, we examined how the previously uncharacterized gene, hEx, functions within this pathway. Importantly, this thesis characterizes hEx as a putative tumor suppressor showing that it can inhibit cell proliferation, sensitize cancer cells to Taxol treatment as well as inhibit tumor growth in nude mice. However, unlike Drosophila expanded, hEx functions independently of the Hippo-LATS pathway, suggesting that the mammalian signaling pathway is more complicated. The research findings from this thesis enhance our knowledge of the Hippo-LATS pathway in tumorigenesis by elucidating new functions and mechanisms of LATS functions as well as by exploring how upstream components function in relation to this pathway.