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These results suggest Salvador enhances the effects of Hippo kinase activity at multiple points in the Hippo pathway.
Here, the authors discover SAV1-mediated inhibition of the PP2A complex STRIPAK(SLMAP) as a key mechanism of MST1/2 activation.
WW45 has suppressive roles in lung cancer through a pathway involving Hedgehog/Gli1 signaling.
SAV1 represses the activation of the Akt-mTOR signalling, and rapamycin treatment blunts the effects of SAV1 on in vitro and in vivo growth of colorectal cancer cells.
using an Mst2 mutation that disrupts homotypic dimerization, we showed that the monomeric Mst2-SARAH domain could form a stable complex of 1:1 stoichiometric ratio with WW45 refolded under acidic pH.
MST1/2-SAV1 associates with the NPHP transition-zone complex, promoting ciliary localization of multiple ciliary cargoes.
Mst2 and the Ser-3 residue of human WW45 function independently of each other in the regulation of the stability of human WW45.
We also confirmed the interaction of HAX-1 and hSav1 in mammalian cells.
downregulation of SAV1 and the consequent YAP1 activation are involved in the pathogenesis of high-grade clear cell renal cell carcinoma.
MST and hSAV act as novel co-regulators of ERalpha and may play an important role in breast cancer pathogenesis.
hSav1 interacts with HAX1 and attenuates its protective role against apoptosis in MCF-7 breast cancer cells.
a role for Salvador as a human tumor suppressor and RASSF1A effector and show that Salvador allows RASSF1A to modulate p73 independently of the hippo pathway.
Study reports that two Hippo pathway components, Mst2 and the scaffold protein hSav1, directly interact with Nek2A and regulate its ability to localize to centrosomes, and phosphorylate C-Nap1 and rootletin.
hSav1 is a newly identified protein that interacts with Mst1 and augments Mst1-mediated apoptosis.
Salvador gene is not frequently mutated in human carcinoma tissues.
Together these results show that hSav can bind to, and be phosphorylated by, Mst, and that the stabilizing effect of Mst on hSav requires its interaction with hSav but is probably not due to phosphorylation of hSav by Mst.
hWW45 is required to enhance MST1-mediated apoptosis in vivo and thus is a critical player in an MST1-driven cell death signaling pathway.
deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls
Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis.
Differentiation of 3T3-L1 cells was augmented by MST2 and SAV1 expression and inhibited by knockdown of MST1/2 or SAV1.
In this study, they investigated epigenetic characteristics of WW45+/- mice, evaluating time-dependent changes from prior to the onset of tumorigenesis to hepatocarcinoma.
show that mice with liver-specific ablation of WW45 (a homolog of Drosophila Salvador and adaptor for the Hippo kinase) manifest increased liver size and expansion of hepatic progenitor cells (oval cells) and eventually develop hepatomas.
show using a conditional allele of sav1, that an adaptor that potentiates mst1 and mst2 activity is likewise required to suppress growth in the mature liver and to prevent tumor formation.
While typical WW domains function as monomeric modules that recognize proline-rich sequences, by using conserved residues that are solvent-exposed on the surface of the beta-sheet, this WW domain buries these residues in the dimer interface.
Mice lacking WW45 reveal a crucial role for WW45 in cell-cycle exit and epithelial terminal differentiation.
WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein with two WW domains, a SARAH domain, and a coiled-coil region and is ubiquitously expressed in adult tissues. This protein binds to MST1 (mammalian sterile 20-like kinase 1) and promotes MST1-induced apoptosis. It has also been shown to bind to HAX1 (hematopoietic cell-specific protein 1 (HS1)-associated protein X-1) and to attenuate the anti-apoptotic effects of HAX1. Studies in human and mouse suggest this gene acts as a tumor suppressor.
, 45 kDa WW domain protein
, WW domain-containing
, protein salvador homolog 1
, WW domain-containing protein 3
, WW domain-containing protein 4
, Salvador homolog 1 protein