Phosphorylation of SAV1 by mammalian ste20-like kinase promotes cell death

Park, Byoung Hee; Lee, Yong Hee

doi:10.5483/bmbrep.2011.44.9.584

Cited by 20 publications

(14 citation statements)

References 26 publications

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“…Coexpression of Hippo with Sav or Lats results in the phosphorylation of both, whereas expression of all three further enhances Lats (but not Sav) phosphorylation, as visualized by electrophoretic slowing; the Hippo and Sav SARAH domains are required for this effect[11]. Similar responses are reported with coexpression of WW45, Lats1 and Mst2 [57,71]. The impact of WW45 on the regulation of Mst1 and Lats1/2 in more physiologic conditions was examined in mouse primary embryonic keratinocytes, which can be induced to differentiate by addition of Ca ++ at mM levels.…”

Section: The “Hippo” Kinases Hippo Mst1 and Mst2mentioning

confidence: 79%

Protein kinases of the Hippo pathway: Regulation and substrates

Avruch

Zhou

Fitamant

et al. 2012

Seminars in Cell & Developmental Biology

211

197

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The “Hippo” signaling pathway has emerged as a major regulator of cell proliferation and survival in metazoans. The pathway, as delineated by genetic and biochemical studies in Drosophila, consists of a kinase cascade regulated by cell-cell contact and cell polarity that inhibits the transcriptional coactivator Yorkie and its proliferative, anti-differentiation, antiapoptotic transcriptional program. The core pathway components are the GC kinase Hippo, which phosphorylates the noncatalytic polypeptide Mats/Mob1 and, with the assistance of the scaffold protein Salvador, phosphorylates the ndr-family kinase Lats. In turn phospho-Lats, after binding to phospho-Mats, autoactivates and phosphorylates Yorkie, resulting in its nuclear exit. Hippo also uses the scaffold protein Furry and a different Mob protein to control another ndr-like kinase, the morphogenetic regulator Tricornered. Architecturally homologous kinase cascades consisting of a GC kinase, a Mob protein, a scaffolding polypeptide and an ndr-like kinase are well described in yeast; in S. cerevisiae e.g., the MEN pathway promotes mitotic exit whereas the RAM network, using a different GC kinase, Mob protein, scaffold and ndr-like kinase, regulates cell polarity and morphogenesis. In mammals, the Hippo orthologues Mst1 and Mst2 utilize the Salvador ortholog WW45/Sav1 and other scaffolds to regulate the kinases Lats1/Lats2 and ndr1/ndr2. As in Drosophila, murine Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in the epithelial cells of the liver and gut; loss of both Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be largely negated by reduction or elimination of YAP. Despite this conservation, considerable diversification in pathway composition and regulation is already evident; in skin e.g., YAP phosphorylation is independent of Mst1Mst2 and Lats1Lats2. Moreover, in lymphoid cells, Mst1/Mst2, under the control of the Rap1 GTPase and independent of YAP, promotes integrin clustering, actin remodeling and motility while restraining the proliferation of naïve T cells. This review will summarize current knowledge of the structure and regulation of the kinases Hippo/Mst1&2, their noncatalytic binding partners, Salvador and the Rassf polypeptides, and their major substrates Warts/Lats1&2, Trc/ndr1&2, Mats/Mob1 and FOXO.

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Section: The “Hippo” Kinases Hippo Mst1 and Mst2mentioning

confidence: 79%

Protein kinases of the Hippo pathway: Regulation and substrates

Avruch

Zhou

Fitamant

et al. 2012

Seminars in Cell & Developmental Biology

211

197

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“…Since Sav ubiquitylation occurs in the C-terminal domain responsible for Hpo binding, Hpo could sterically interfere with ubiquitin ligase binding or ubiquitin transfer. Alternatively, since Hpo is known to phosphorylate Sav ([ 7 , 9 , 45 , 46 , 51 ] and this report), phosphorylation might prevent ligase binding or ubiquitylation. To investigate these possible mechanisms, we analysed the effect of several Hpo truncations and mutants on Sav ubiquitylation ( Fig 3 A ).…”

Section: Resultsmentioning

confidence: 87%

Hippo Stabilises Its Adaptor Salvador by Antagonising the HECT Ubiquitin Ligase Herc4

et al. 2015

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Signalling through the Hippo (Hpo) pathway involves a kinase cascade, which leads to the phosphorylation and inactivation of the pro-growth transcriptional co-activator Yorkie (Yki). Despite the identification of a large number of pathway members and modulators, our understanding of the molecular events that lead to activation of Hpo and the downstream kinase Warts (Wts) remain incomplete. Recently, targeted degradation of several Hpo pathway components has been demonstrated as a means of regulating pathway activity. In particular, the stability of scaffold protein Salvador (Sav), which is believed to promote Hpo/Wts association, is crucially dependent on its binding partner Hpo. In a cell-based RNAi screen for ubiquitin regulators involved in Sav stability, we identify the HECT domain protein Herc4 (HECT and RLD domain containing E3 ligase) as a Sav E3 ligase. Herc4 expression promotes Sav ubiquitylation and degradation, while Herc4 depletion stabilises Sav. Interestingly, Hpo reduces Sav/Herc4 interaction in a kinase-dependent manner. This suggests the existence of a positive feedback loop, where Hpo stabilises its own positive regulator by antagonising Herc4-mediated degradation of Sav.

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“…This result suggested that the core members of the Hippo pathway, comprising at least one of the upstream Ste-20 kinases (STK4 and STK3), SAV1 and LATS1 as well as MOB2 molecule might form a larger and more complex functional compound in which SAV1 serves as a connector to assembly them together through a mode of action similar to the previously reported in mammals [ 47 ]. Furthermore, the SAV1 molecule was reported to have several phosphorylation residues that were phosphorylated by MST in human [ 33 , 34 , 35 ]. In this study, we found that chicken SAV1 was also phosphorylated by SKT4 or SKT3 kinase of the Hippo/MST pathway in the GCs of the developing ovarian follicles, and the phosphorylated SAV1 was able to significantly enhance the phosphorylation levels of LATS1 induced by the kinase of STK4 or STK3 in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the phosphorylation of chicken SAV1 mediated by the Ser/Thr protein kinase STK4 or STK3 may be most important in the regulation of oocyte maturation and granular cell proliferation during ovarian follicle growth by the Hippo/MST pathway. As for whether the detailed phosphorylated residues within the chicken SAV1 is consistent to those having been determined in mammals [ 35 ], further studies will be required to address this possibility.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that SAV1 recruits LATS to the MST to promote the phosphorylation of LATS mediated by MST1 (homologue of Ser/Thr kinase 4, STK4 in chicken) and MST2 (STK3 in chicken) [ 30 , 31 ], and that SAV1 is required for the correct cellular localization and function of MST [ 32 ]. Moreover, SAV1 has been reported to have several phosphorylation residues that were phosphorylated by MST in human [ 33 , 34 ]; the phosphorylation of SAV1 by MSTs promotes cell death [ 35 ]. Structural analysis has identified that SAV1 having the domains permits protein-protein interaction, including 2 WW domains and a coiled-coil motif in its C-terminus, which suggest that SAV1 functions as a scaffold in a multimeric complex [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

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The Hippo/MST Pathway Member SAV1 Plays a Suppressive Role in Development of the Prehierarchical Follicles in Hen Ovary

Qin

Tyasi

et al. 2016

PLoS ONE

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The Hippo/MST signaling pathway is a critical player in controlling cell proliferation, self-renewal, differentiation, and apoptosis of most tissues and organs in diverse species. Previous studies have shown that Salvador homolog 1 (SAV1), a scaffolding protein which functions in the signaling system is expressed in mammalian ovaries and play a vital role in governing the follicle development. But the exact biological effects of chicken SAV1 in prehierarchical follicle development remain poorly understood. In the present study, we demonstrated that the SAV1 protein is predominantly expressed in the oocytes and undifferentiated granulosa cells in the various sized prehierarchical follicles of hen ovary, and the endogenous expression level of SAV1 mRNA appears down-regulated from the primordial follicles to the largest preovulatory follicles (F2-F1) by immunohistochemistry and real-time RT-PCR, respectively. Moreover, we found the intracellular SAV1 physically interacts with each of the pathway members, including STK4/MST1, STK3/MST2, LATS1 and MOB2 using western blotting. And SAV1 significantly promotes the phosphorylation of LATS1 induced by the kinase of STK4 or STK3 in vitro. Furthermore, SAV1 knockdown by small interfering RNA (siRNA) significantly increased proliferation of granulosa cells from the prehierarchical follicles (6–8 mm in diameter) by BrdU-incorporation assay, in which the expression levels of GDF9, StAR and FSHR mRNA was notably enhanced. Meanwhile, these findings were consolidated by the data of SAV1 overexpression. Taken together, the present results revealed that SAV1 can inhibit proliferation of the granulosa cells whereby the expression levels of GDF9, StAR and FSHR mRNA were negatively regulated. Accordingly, SAV1, as a member of the hippo/MST signaling pathway plays a suppressive role in ovarian follicle development by promoting phosphorylation and activity of the downstream LATS1, may consequently lead to prevention of the follicle selection during ovary development.

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Phosphorylation of SAV1 by mammalian ste20-like kinase promotes cell death

Cited by 20 publications

References 26 publications

Protein kinases of the Hippo pathway: Regulation and substrates

Protein kinases of the Hippo pathway: Regulation and substrates

Hippo Stabilises Its Adaptor Salvador by Antagonising the HECT Ubiquitin Ligase Herc4

The Hippo/MST Pathway Member SAV1 Plays a Suppressive Role in Development of the Prehierarchical Follicles in Hen Ovary

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