Tumor Suppressor LATS1 Is a Negative Regulator of Oncogene YAP

Abstract

LATS (large tumor suppressor) or warts is a Ser/Thr kinase that belongs to the Ndr/LATS subfamily of AGC (protein kinase A/PKG/PKC) kinases. It is a tumor suppressor gene originally isolated from Drosophila and recently isolated from mice and humans. Drosophila or mice mutant for LATS develop tumors in various tissues. Recent studies in Drosophila demonstrate that LATS is a central player of an emerging tumor suppressor pathway called the Hippo-LATS/Warts pathway that suppresses tumor growth by regulating cell proliferation, cell growth, and cell death. Although tremendous progress has been made toward understanding the roles of LATS in tumorigenesis, the kinase substrates of LATS or downstream target proteins mediating LATS function remain largely unknown. In this study, we have provided convincing evidence that the LATS1 tumor suppressor can bind to and phosphorylate transcription regulator and oncogene YAP in vitro and in vivo. We have also identified HX(R/H/K)XX(S/T) as the consensus phosphorylation sequence for LATS/Ndr kinase substrates. Significantly, we have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP. Finally, by using microarray analysis, we have also identified many oncogenes or tumor suppressor genes up-regulated or down-regulated by YAP. These research findings will have profound impacts on our understanding of the molecular mechanism of the LATS tumor suppressor and the emerging Hippo-LATS/Warts pathway.

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

“…PhosphoYap appeared with several upshifted bands, likely representing incremental phosphorylation of the five different Lats2 sites on Yap. 9,28 Analysis of mRNA by qPCR confirmed expression of the untagged Mst1 and WW45 ( Supplementary Figures 3a and b). Furthermore, qPCR showed that expression of endogenous CTGF, a target gene of Yap, increased with Yap overexpression, but was inhibited with Lats2, and was inhibited further when Lats2 was expressed together with Mst1 and WW45 (Figure 3b).…”

“…Upon Hippo pathway activation, Lats phosphorylates Yap at Ser 127 . 9,28,29 In the densely plated cells, phosphorylation of Yap at Ser 127 was detected, demonstrating that the Hippo pathway was active (Figures 1b-d). To demonstrate that inhibition of apoptosis at high cell density was not cell type specific, we tested other cell lines.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Activated Lats1/2 in turn phosphorylate YAP/TAZ transcription co-activators on several residues (Dong et al, 2007;Zhao et al, 2007;Hao et al, 2008;Lei et al, 2008;Oka et al, 2008). Phosphorylation of S127 in YAP promotes 14-3-3 binding, resulting in cytoplasmic sequestration and therefore inactivation of YAP (Dong et al, 2007;Zhao et al, 2007;Hao et al, 2008;Lei et al, 2008;Oh and Irvine, 2008). Indeed, mutation of S127 and disruption of 14-3-3 binding lead to activation of YAP (Zhao et al, 2007), confirming the inhibitory nature of this phosphorylation.…”

“…CTGF alone, however, does not account for all YAP phenotypes. YAP and TAZ also induce the expression of AREG (Zhang et al, 2009b) and FGF1 (Hao et al, 2008), which may also mediate non-cell-autonomous function of the Hippo pathway. However, the mechanisms underlying the induction of these genes, including the responsible transcription factors, are mostly unclear.…”

c-Abl antagonizes the YAP oncogenic function

“…9 Through these mechanisms the transcriptional activity of YAP is downregulated under conditions of high cell density. 6,10 Although many studies on the nonreceptor tyrosine kinase c-Abl (Abelson murine leukemia viral oncogene) are focused on its role as an oncogene as part of the fusion protein BCRAbl, 11 it is also known to play a role in the DNA damage response. 12 Once activated, c-Abl can promote apoptosis or induce cell cycle arrest through the phosphorylation and activation of p73, 13,14 a p53 paralog.…”