Monopolar spindle-one-binder protein 2 regulates the activity of large tumor suppressor/yes-associated protein to inhibit the motility of SMMC-7721 hepatocellular carcinoma cells

Abstract

Abstract. Accumulating evidence implicates monopolar spindle-one-binder protein (MOB)2 as an inhibitor of nuclear-Dbf2-related kinase (NDR) by competing with MOB1 for interaction with NDR1/2. NDR/large tumor suppressor (LATS) kinases may function similarly to yes-associated protein (YAP) kinases and be considered as members of the Hippo core cassette. MOB2 appears to serve roles in cell survival, cell cycle progression, responses to DNA damage and cell motility. However, the underlying mechanisms involved remain unclarified. In the present study, it was demonstrated that the knockout of MOB2 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 promoted migration and invasion, induced phosphorylation of NDR1/2 and decreased phosphorylation of YAP in SMMC-7721 cells when compared with the blank vector-transduced cells. By contrast, the overexpression of MOB2 resulted in the opposite results. Mechanistically, MOB2 regulated the alternative interaction of MOB1 with NDR1/2 and LATS1, which resulted in increased phosphorylation of LATS1 and MOB1 and thereby led to the inactivation of YAP and consequently inhibition of cell motility. The results of the present study provide evidence of MOB2 serving a positive role in LATS/YAP activation by activating the Hippo signaling pathway.

Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways

“…Additional functions for NDR kinases and Mobs are just beginning to show up from unbiased screens in distinct cell types, whether based on traditional genetics, RNAi, chemical genetics or protein-protein interactions. The potential for crossregulation and/or competition between Warts/LATS kinases and Tricornered-like kinases is apparent through their regulation by shared Class I Mob and Hippo activators but is only beginning to be investigated in detail (Zhang et al, 2018). Our understanding of both Mobs and Hippo pathway signaling would benefit from experiments to directly test whether a Mob-NDR kinase partnership and STRIPAK antagonism influence the pathway output in each new cellular context.…”

MOB (Mps one Binder) Proteins in the Hippo Pathway and Cancer

“…More specifically, it was documented that hMOB2 could compete with hMOB1 for NDR1/2 binding, with hMOB2 counteracting hMOB1 as a co-activator of NDR1/2 [1,35,61]. In this context, Zhang et al studied Hippo signalling in a hMOB2 knockout hepatocellular carcinoma (HCC) cell line [62]. They found that MST1/2-mediated phosphorylation of NDR1/2 was induced, while MST1/2-mediated phosphorylations of hMOB1 and LATS1/2 were decreased upon hMOB2 knockout [62].…”

“…In this context, Zhang et al studied Hippo signalling in a hMOB2 knockout hepatocellular carcinoma (HCC) cell line [62]. They found that MST1/2-mediated phosphorylation of NDR1/2 was induced, while MST1/2-mediated phosphorylations of hMOB1 and LATS1/2 were decreased upon hMOB2 knockout [62]. LATS1/2-mediated phosphorylation of YAP was also reduced in hMOB2 knockout cells, while MOB2 overexpression resulted in opposite effects [62].…”

“…They found that MST1/2-mediated phosphorylation of NDR1/2 was induced, while MST1/2-mediated phosphorylations of hMOB1 and LATS1/2 were decreased upon hMOB2 knockout [62]. LATS1/2-mediated phosphorylation of YAP was also reduced in hMOB2 knockout cells, while MOB2 overexpression resulted in opposite effects [62]. Subsequently, the authors concluded that loss of hMOB2 can favour hMOB1 binding to NDR1/2, thereby reducing the pool of hMOB1 available for LATS1/2 binding.…”

“…Subsequently, the authors concluded that loss of hMOB2 can favour hMOB1 binding to NDR1/2, thereby reducing the pool of hMOB1 available for LATS1/2 binding. Conversely, hMOB2 overexpression may reduce hMOB1 binding to NDR1/2, thereby freeing hMOB1 to bind to LATS, resulting in the activation of Hippo signalling upstream of YAP [62]. However, this study [62] did not examine whether this molecular reprogramming of binding partners could be a possible consequence of cell cycle effects upon hMOB2 loss-of-function.…”