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: 9.92). 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.

0 Followers
 · 
74 Views
  • Source
    • "The first clue that the Hippo signaling pathway could be directly contributing to mitotic progression came from a study reporting that the activity of MST1 and MST2, two essential kinases of the Hippo pathway in mammalian cells, increases during mitosis, and that this effect was enhanced by microtubule-depolymerizing drugs (Praskova et al., 2008). A subsequent study reported that depletion of NDR1, a downstream target of MST kinases, causes MST2-dependent mitotic chromosome misalignment in HeLa cells (Chiba et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Most solid tumors are characterized by abnormal chromosome numbers (aneuploidy) and karyotypic profiling has shown that the majority of these tumors are heterogeneous and chromosomally unstable. Chromosomal instability (CIN) is defined as persistent mis-segregation of whole chromosomes and is caused by defects during mitosis. Large-scale genome sequencing has failed to reveal frequent mutations of genes encoding proteins involved in mitosis. On the contrary, sequencing has revealed that most mutated genes in cancer fall into a limited number of core oncogenic signaling pathways that regulate the cell cycle, cell growth, and apoptosis. This led to the notion that the induction of oncogenic signaling is a separate event from the loss of mitotic fidelity, but a growing body of evidence suggests that oncogenic signaling can deregulate cell cycle progression, growth, and differentiation as well as cause CIN. These new results indicate that the induction of CIN can no longer be considered separately from the cancer-associated driver mutations. Here we review the primary causes of CIN in mitosis and discuss how the oncogenic activation of key signal transduction pathways contributes to the induction of CIN.
    Frontiers in Oncology 06/2013; 3:164. DOI:10.3389/fonc.2013.00164
  • Source
    • "Mats also belongs to the NDR family and binds Wts, potentiating its intrinsic activity (Lai et al., 2005). Hpo phosphorylates Mats, increasing its binding affinity to Wts and potentiating Wts kinase activity (Praskova et al., 2008). Located upstream of the Hpo pathway are Merlin (Mer) and Expanded (Ex; Boedigheimer et al., 1993; LaJeunesse et al., 1998; Hamaratoglu et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Growth arrest, inhibition of cell proliferation, apoptosis, senescence, and differentiation are the most characterized effects of a given tumor suppressor response. It is becoming increasingly clear that tumor suppression results from the integrated and synergistic activities of different pathways. This implies that tumor suppression includes linear, as well as lateral, crosstalk signaling. The latter may happen through the concomitant involvement of common nodal proteins. Here, we discuss the role of Promyelocytic leukemia protein (PML) in functional cross-talks with the HIPPO and the p53 family tumor suppressor pathways. PML, in addition to its own anti-tumor activity, contributes to the assembly of an integrated and superior network that may be necessary for the maximization of the tumor suppressor response to diverse oncogenic insults.
    Frontiers in Oncology 03/2013; 3:36. DOI:10.3389/fonc.2013.00036
  • Source
    • "Sav1/WW45 is a WW domain-containing scaffold protein that binds Mst1/2 and Lats, through their respective SARAH coiled coil domains, thereby promoting Mst1/2 phosphorylation of Lats (Hwang et al., 2007). Mst1/2 also phosphorylates Mob1A/B (Wei et al., 2007; Praskova et al., 2008), which enhances Mob1's ability to bind and activate Lats1/2. Lats1/2 phosphorylates YAP (or TAZ, depending on the cellular context), which promotes 14-3-3 binding to YAP, causing YAP nuclear exit, and thus inhibition of its function. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hippo pathway plays a crucial role in controlling organ size by inhibiting cell proliferation and promoting cell death. Recent findings implicate that this pathway is involved in the process of intestinal regeneration and tumorigenesis. Here we summarize current studies for the function of the Hippo signaling pathway in intestinal homeostasis, regeneration and tumorigenesis, and the crosstalk between the Hippo signaling pathway and other major signaling pathways, i.e. Wnt, Notch and Jak/Stat signaling pathways in intestinal compartment.
    Protein & Cell 04/2012; 3(4):305-10. DOI:10.1007/s13238-012-2913-9 · 2.85 Impact Factor
Show more