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  • br Author contributions br Declaration


    Author contributions
    Declaration of conflict of interest
    Acknowledgements We are grateful to the Director, National Institute of Immunology for his support. The work was partially supported by J.C. Bose Fellowship to SSM. We acknowledge the help from staff of Small Animal Facility of National Institute of Immunology.
    Introduction The Hippo pathway was originally identified in functional genetic screens in Drosophila as a mechanism controlling organ size via inhibition of cell proliferation and induction of apoptosis (Justice et al., 1995). Although slight variations in the phenotypes were observed, mutants of the pathway components shared a strong overgrowth phenotype. Contact inhibition of proliferation is a phenomenon whereby normal Mouse HGF / Hepatocyte Growth Factor Protein (His Tag) in monolayers exhibit reduced proliferation, even growth arrest, when establishing cell–cell contacts. This property is often lost during neoplastic progression. Clues regarding the mechanisms by which cells sense contacts with other cells and mediates contact inhibition of proliferation have emerged over the recent years, and the Hippo signaling pathway has been identified as a major player in this process (Zhao et al., 2007). It is broadly accepted that the Hippo pathway exerts critical tumor suppressor activity, a large part of it likely linked to its implication in the control of contact inhibition. Upstream members of the cascade (kinases) are often mutated or have decreased expression in various cancers, while nuclear accumulation and/or overexpression of YAP and TAZ (Hippo substrates) is often observed in tumors (Pan 2010; Bao et al., 2011; Piccolo et al., 2013; Nallet-Staub et al., 2015). The canonical Hippo pathway consists of a core serine kinase cascade and associated scaffolding proteins that respond to various environmental cues such as mechanotransduction, cell-matrix adhesion as well as cell–cell contacts. In mammals, the core kinase cascade consisting in MST1/2 and LATS1/2 kinases is modulated by scaffolding proteins, SAV1 and MOB1, both of which work to promote Hippo pathway signaling. When activated, MST1/2 (Hippo homologs) phosphorylate the downstream kinases LATS1/2 (non-existent in Drosophila) (Hergovich and Hemmings 2009). Activated LATS1/2 directly interact and phosphorylate YAP and TAZ (Yorkie homologs) on Ser127 and Ser89 respectively (Zhang et al., 2008), these events respectively leading to binding of TAZ/YAP to 14-3-3 proteins and subsequent cytoplasmic sequestration and/or proteasomal degradation (reviewed in (Zhang et al., 2009; Mauviel et al., 2012)). When Hippo kinases are inactive, YAP and TAZ are hypo-phosphorylated and accumulate in the nucleus. YAP/TAZ do not have a DNA binding domain and function as transcriptional co-activators for various transcription factors, most importantly TEAD family members (Zhang et al., 2009). The above steps are summarized in Fig. 1. A transcriptional co-repressor function of YAP and TAZ was also identified, whereby Mouse HGF / Hepatocyte Growth Factor Protein (His Tag) a TEAD/YAP/TAZ complex deacetylates histones and alters nucleosome occupancy of target genes by recruiting the NuRD complex, leading to the repression of DDIT4 and Trail expression, thereby promoting cell survival (Kim et al., 2015). Noteworthy, Hippo pathway components are highly conserved across species and play a similar role in cell growth and organ size control. Human YAP, Lats1, Mst2, and Mob1 can functionally rescue the corresponding Drosophila mutants (Huang et al., 2005) and the effect of Hippo pathway on organ size initially identified in Drosophila have been reported in various tissues using conditional knockout experiments in mice (Camargo et al., 2007; Zhang et al., 2010; Del Re et al., 2013). Despite widespread redundancy between YAP and TAZ functions, there is more and more functional evidence that discriminate these two Hippo pathway family members in various setting. Thus, the TAZ/YAP nomenclature will only be used in instances where both proteins can substitute for each other.