salvador Promotes Both Cell Cycle Exit and Apoptosis in Drosophila and Is Mutated in Human Cancer Cell Lines

Abstract

The number of cells in an organism is determined by regulating both cell proliferation and cell death. Relatively few mechanisms have been identified that can modulate both of these processes. In a screen for Drosophila mutations that result in tissue overgrowth, we identified salvador (sav), a gene that promotes both cell cycle exit and cell death. Elevated Cyclin E and DIAP1 levels are found in mutant cells, resulting in delayed cell cycle exit and impaired apoptosis. Salvador contains two WW domains and binds to the Warts (or LATS) protein kinase. The human ortholog of salvador (hWW45) is mutated in three cancer cell lines. Thus, salvador restricts cell numbers in vivo by functioning as a dual regulator of cell proliferation and apoptosis.

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

“…Lats2 is also found mutated in human mesothelioma cell lines and non-small cell lung cancer (Strazisar et al, 2009;Murakami et al, 2011). Additionally, Sav1 and Mob1 mutations have been observed in human cancer cell lines and skin melanomas, respectively (Tapon et al, 2002;Lai et al, 2005). Together, these studies highlight a significant role of the Hippo pathway in organ size regulation and tumorigenesis.…”

“…Extensive research has led to the identification of the Hippo tumor suppressor pathway as a key regulator of organ size in Drosophila and mammals (Pan, 2010). By genetic mosaic screens, mutation of the first batch of Hippo pathway genes warts (wts) (Justice et al, 1995;Xu et al, 1995), hippo (hpo) (Harvey et al, 2003;Jia et al, 2003;Pantalacci et al, 2003;Udan et al, 2003;Wu et al, 2003), and salvador (sav) (Kango-Singh et al, 2002;Tapon et al, 2002) were found to dramatically promote tissue overgrowth and organ size enlargement. These genes belong to the hyperplastic group of Drosophila tumor suppressors wherein mutations of these genes result in robust tissue overgrowth without alterations of cell fate determination or cell polarity (Hariharan and Bilder, 2006).…”

“…Scalloped (Sd), the homolog of mammalian TEAD family transcription factors, were found to be critical partners of Yki in the regulation of gene expression (Goulev et al, 2008;Wu et al, 2008;Zhang et al, 2008;Zhao et al, 2008;Zhang et al, 2009a). Several transcriptional targets of the Hippo pathway have been identified, including cyclin E, which directly promotes cell cycle progression and cell proliferation, and diap1, which inhibits apoptosis (Tapon et al, 2002;Jia et al, 2003;Udan et al, 2003;Wu et al, 2003;Lai et al, 2005). The Hippo pathway also inhibits expression of a microRNA bantam to affect organ size, although the downstream effector of bantam is not clear.…”

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

“…In budding and fission yeast, the scaffolding proteins Nud1p and Cdc11p/Sid4p support MEN and SIN signalling, respectively [10,11,16]. In flies, the scaffolding protein Salvador (Sav; the fly counterpart of Nud1p and Cdc11p/Sid4p) functions as a central tumour suppressor in Hippo signalling [26,[55][56][57][58]70]. However, the involvement of Sav in mitotic processes is yet to be tested.…”

Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1

“…Mats binds Warts and stimulates its kinase activity (He et al, 2005;Lai et al, 2005). Sav interacts through its WW-domains with the PPXY motif of Warts and functions as a scaffold to form the tripartite complex of Hippo, Sav and Warts (Tapon et al, 2002;Harvey et al, 2003). These studies lead to the hypothesis that Hippo/Sav complex activates Warts/ Mats complex.…”