Article

MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation

Diabetes Unit and Medical Services and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Current Biology (Impact Factor: 9.57). 04/2008; 18(5):311-21. DOI: 10.1016/j.cub.2008.02.006
Source: PubMed

ABSTRACT

MST1 and MST2 are the mammalian Ste20-related protein kinases most closely related to Drosophila Hippo, a major regulator of cell proliferation and survival during development. Overexpression of MST1 or MST2 in mammalian cells is proapototic; however, little is known concerning the physiologic regulation of the endogenous MST1/MST2 kinases, their role in mammalian cell proliferation, or the identity of the MST1/MST2 substrates critical to proliferative regulation.
We show that MST1 and MST2 activity increases during mitosis, especially in nocodazole-arrested mitotic cells, where these kinases exhibit both an increase in both abundance and activation. MST1 and MST2 also can be activated nonphysiologically by okadaic acid or H2O2. The MOBKL1A and MOBKL1B polypeptides, homologs of the Drosophila MATS polypeptide, are identified as preferred MST1/MST2 substrates in vitro and are phosphorylated in cells in an MST1/MST2-dependent manner in mitosis and in response to okadaic acid or H2O2. MST1/MST2-catalyzed MOBKL1A/MOBKL1B phosphorylation alters the ability of MOBKL1A/MOBKL1B to bind and regulate downstream targets such as the NDR-family protein kinases. Thus, MOBKL1A/MOBKL1B phosphorylation in cells promotes MOBKL1A/MOBKL1B binding to the LATS1 kinase and enables H2O2-stimulated LATS1 activation loop phosphorylation. Most importantly, replacement of endogenous MOBKL1A/MOBKL1B by a nonphosphorylatable mutant is sufficient to accelerate cell proliferation substantially by speeding progression through G1/S as well as mitotic exit.
These results establish that MST1 and MST2 are activated in mitosis and catalyze the mitotic phosphorylation of MOBKL1A/MOBKL1B. MOBKL1A/MOBKL1B phosphorylation, in turn, is sufficient to inhibit proliferation through actions at several points in the cell cycle.

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    • "Therefore, it is possible that MST1/2 activation can be initiated by dimerization and does not neccesarily require upstream kinases. Active MST1/2 phosphorylate SAV1 (homolog of Drosophila Salvador [Sav]) and MOB1A/B (homologs of Drosophila Mats) (Callus et al. 2006; Praskova et al. 2008 ), two scaffold proteins that assist MST1/2 in the recruitment and phosphorylation of LATS1/2 at their hydrophobic motifs (T1079 for LATS1 and T1041 for LATS2) (Hergovich et al. 2006; Yin et al. 2013 ). Another key player in this action is NF2/Merlin, which directly interacts with LATS1/ 2 and facilitates LATS1/2 phosphorylation by the MST1/ 2–SAV1 complex (Yin et al. 2013). "
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    ABSTRACT: The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell– cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.
    Full-text · Article · Jan 2016 · Genes & Development
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    • "For example, by stimulating the activating PPI between MOB1 and LATS1/2 [9], an efficient decrease of YAP/TAZ activities might be obtained. We envision that this could be achieved by either increasing MOB1 phosphorylation by MST1/2, known to increase LATS1/2-MOB1 interactions [105], or by generating a MOB1-independent active LATS variant. In this sense, modified LATS kinases functioning independent of MOB1 and MST1/2 signalling maybe can be designed as recently described for the LATS-related NDR1 kinase [106]. "
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    ABSTRACT: The Hippo tumour suppressor pathway co-ordinates cell proliferation, cell death and cell differentiation to regulate tissue growth control. In mammals, a conserved core Hippo signalling module receives signal inputs on different levels to ensure the proper regulation of YAP/TAZ activities as transcriptional co-activators. While the core module members MST1/2, Salvador, LATS1/2 and MOB1 have been attributed tumour suppressive functions, YAP/TAZ have been mainly described to have oncogenic roles, although some reports provided evidence supporting growth suppressive roles of YAP/TAZ in certain cancer settings. Intriguingly, mammalian Hippo signalling is also implicated in non-cancer diseases and plays a role in tissue regeneration following injury. Cumulatively, these findings indicate that the pharmacological inhibition or activation of the Hippo pathway could be desirable depending on the disease context. In this review, we first summarise the functions of the mammalian Hippo pathway in tumour formation, and then discuss non-cancer diseases involving Hippo signalling core components with a specific focus on our current understanding of the non-cancer roles of MST1/2 and YAP/TAZ. In addition, the pros and cons of possible pharmacological interventions with Hippo signalling will be reviewed, with particular emphasis on anti-cancer drug development and regenerative medicine.
    Full-text · Article · Jul 2014 · Clinical and Translational Medicine
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    • "Importantly, these regulatory mechanisms are more complicated in mammalian cells. MST1/2 kinases also phosphorylate hMOB1A/B on Thr12 and Thr35, thereby increasing the affinity of hMOB1A/B towards NDR1/2 [58]. Moreover, NDR1 deficient in hMOB1A/B binding cannot be phosphorylated by MST1 on Thr444 in S-phase arrested cells [43], suggesting that hMOB1A/B binding to NDR1/2 is required for the phosphorylation of both regulatory sites in human cells [39]. "
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    ABSTRACT: The metazoan Hippo pathway is an essential tumour suppressor signalling cascade that ensures normal tissue growth by co-ordinating cell proliferation, cell death and cell differentiation. Over the past years, various genetic and biochemical studies in Drosophila and mammals have defined a conserved core Hippo signalling module, composed of members of the Ste20-like kinase, the MOB co-activator and the AGC kinase families. In Drosophila, stimulated Hippo kinase phosphorylates and thereby activates the Mats/Warts complex, which consequently phosphorylates and inactivates the transcriptional co-activator Yorkie. In mammals, the counterparts of the Hippo/Mats/Warts/Yorkie cascade, namely MST1/2, MOB1A/B, LATS1/2 and YAP/TAZ, function in a similar fashion. These canonical Hippo pathways are so highly conserved that human MST2, hMOB1A and LATS1 can compensate for the loss of Hippo, Mats and Warts in flies. However, recent reports have shown that Hippo signalling is more diverse and complex, in particular in mammals. In this review, we summarize our current understanding of mammalian LATS1/2 kinases together with their closest relatives, the NDR1/2 kinases. The regulation of the LATS/NDR family of kinases will be discussed, followed by a summary of all currently known LATS/NDR substrates. Last, but not least, the biological roles of LATS/NDR kinases will be reviewed with specific emphasis on recent discoveries of canonical and non-canonical LATS/NDR functions in the extended Hippo pathway.
    Full-text · Article · Aug 2013 · Cell and Bioscience
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