Role of Lats1 in tumorigenesis

The Hippo pathway is a conserved pathway that regulates cell growth, organ size and stem cell self-renewal. In mammals it consists of a number of kinases, including Lats1 and Lats2, and the transcriptional coactivators Yap and Taz. Upon activation of the pathway, Lats1 and Lats2 phosphorylate Yap and Taz, thereby preventing their nuclear translocation and inhibitory effects on the transcription of cell-proliferative and anti-apoptotic genes. Downregulation of Lats1 and Lats2, or overexpression of Yap and Taz is frequently observed in human cancers, but the underlying mechanisms are not well understood. On page 508, Hiroshi Nojima and colleagues aim to shed light on the tumour suppressor role of the Hippo pathway by generating knockout mice and cell lines that lack the N-terminal LCD1 region of Lats1 (Lats1^ΔN/ΔN). At their N-termini, Lats1 and Lats 2 have two conversed regions (Lats conserved domains 1 and 2; LCD1 and LCD2), which have been suggested to have a role in tumour suppression. Some Lats1^ΔN/ΔN mice were born, albeit with a very low birth rate, and grow normally. By contrast, Lats1^ΔN/ΔN mouse embryonic fibroblasts displayed dramatic mitotic defects and showed abnormal cell growth, similar to that observed in tumour cells. Importantly, expression of Lats2 was downregulated in these cells, whereas YAP was overexpressed; this results in the stabilisation of YAP, because its phosphorylation by both kinases is required for its inactivation, and, eventually, abnormal growth and tumorigenesis.