<i>Drosophila</i>Mob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

He, Ying; Emoto, Kazuo; Fang, Xiaolan; Ren, Nan; Tian, Xiaojing; Jan, Yuh-Nung; Adler, Paul N.

doi:10.1091/mbc.e05-01-0018

Cited by 79 publications

(132 citation statements)

References 42 publications

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“…One possibility is that Mats functions in complex with Warts in mitosis, as already shown for the control of cell proliferation and death [24,62]. Potentially, Mats could function in mitosis independent of Warts, since Mats can also interact with Trc, the second LATS/NDR kinase in flies [64]. A third possibility is that Mats signals downstream of Hippo independent of LATS/NDR kinases.…”

Section: Hippo Signalling In G2/m In Drosophila Melanogastermentioning

confidence: 85%

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Hergovich

Hemmings

2012

Seminars in Cell & Developmental Biology

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Over the past decade Hippo kinase signalling has been established as an essential tumour suppressor pathway controlling tissue growth in flies and mammals. All members of the Hippo core signalling cassette are conserved from yeast to humans, whereby the yeast analogues of Hippo, Mats and Lats are central components of the mitotic exit network and septation initiation network in budding and fission yeast, respectively. Here, we discuss how far core Hippo signalling components in Drosophila melanogaster and mammals have reported similar mitotic functions as already established for their highly conserved yeast counterparts.

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Section: Hippo Signalling In G2/m In Drosophila Melanogastermentioning

confidence: 85%

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Hergovich

Hemmings

2012

Seminars in Cell & Developmental Biology

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“…Surprisingly, the supplementation of the human dMOB homolog, hMOB1B, into the dMOB1-deficient cells rescued the phenotypes in the mutant flies [59]. Moreover, dMOB1 also regulates the cytoskeletons by interacting with Drosophila trc, a member of the NDR family [58].…”

Section: Mitotic Exit and Cytokinesismentioning

confidence: 99%

“…also been identified as a tumor suppressor [21,58]. Deficiency of dMOB1 has been shown to increase cell proliferation and cause defective apoptosis in addition to the initiation of tumorigenesis due to an excessive amount of cell cycle activator Cyclin E and antiapoptotic protein dIAP (Drosophila inhibitor of apoptosis) [59].…”

Section: Mitotic Exit and Cytokinesismentioning

confidence: 99%

Molecular characterization of human homologs of yeast MOB1

Chow

Hao

Yang

2009

Intl Journal of Cancer

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MOB (Mps One Binder) is a conserved gene family found in all major kingdoms.The MOB genes are essential components acting in mitotic exit and cytokinesis in both budding and fission yeasts. They are further identified as tumor suppressors in Drosophila (D.) melanogaster. Recently, they are found to be involved in the emerging Drosophila Hippo-LATS tumor suppressor pathway. Seven human homologs of yeast MOB (hMOB1A, 1B, 2A, 2B,3,4,5) have been discovered. The hMOB1B is the gene that has been extensively studied and is reported to be required for the activation of LATS (Large Tumor Suppressor)/NDR (Nuclear Dbf2-related) protein kinase family, however, the functional significance of the gene remains unknown. This study is the first to elucidate the biological and biochemical functions of all seven human MOBs. By examining hMOB mRNA expression in various human tissues, we found that the hMOBs have exhibited different expression patterns. We also investigated the subcellular localization of hMOBs during interphase through immunofluorescent analysis. While hMOB2A is localized in the cytoplasm, hMOB4 is exclusively found in the nucleus. All of the other hMOBs are localized in both cytoplasm and nucleus. Furthermore, we identified hMOB1A and hMOB1B as the main binding partners of LATS and NDR in vitro. Additionally, we successfully identified a region on hMOB1B for the interaction with LATS or NDR and determined the crucial residue that is responsible for the binding of LATS2 with hMOB1B. Most significantly, we found that over-expression of hMOB1B in human cancer cells inhibits cell proliferation and induces cell death.Moreover, hMOB1B when targeted to the plasma membrane dramatically enhances the iii phenotype. Conversely, small interfering (si) RNA-mediated suppression of either endogenous hMOB1A or hMOB1B causes increased cell proliferation, whereas suppression of both hMOB1A and hMOB1B demonstrates a more significant enhancement in tumor cell growth. Moreover, co-expression of both LATS and hMOB1B targeted to the plasma membrane completely abolishes cell proliferation. Our findings provide convincing evidence that hMOB1A and hMOB1B function as negative regulators of cell proliferation and as pro-apoptotic proteins. Understanding hMOBs functions in the cell and their possible role in tumorigenesis can provide important information for the diagnosis and treatment of human cancers.iv ACKNOWLEDGEMENTS

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“…Hippo and Sav proteins physically interact with each other through the C-terminal Sav/RASSF/Hippo domain (Harvey et al, 2003;Jia et al, 2003;Pantalacci et al, 2003;Udan et al, 2003;Wu et al, 2003). Mats binds Warts and stimulates its kinase activity (He et al, 2005;Lai et al, 2005). Sav interacts through its WW-domains with the PPXY motif of Warts and functions as a scaffold to form the tripartite complex of Hippo, Sav and Warts (Tapon et al, 2002;Harvey et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…The molecular mechanism to regulate tricornered is less studied. Mats activates Tricornered, but how Hippo and Sav are involved in the regulation is unclear (He et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1

et al. 2008

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Mammalian nuclear Dbf2-related (NDR) kinases (LATS1 and 2, NDR1 and 2) play a role in cell proliferation, apoptosis and morphological changes. These kinases are regulated by mammalian sterile 20-like kinases (MSTs) and Mps one binder (MOB) 1. Okadaic acid (OA), which activates MST2, facilitates the complex formation of MOB1, MST2 and NDR1 in HEK293FT cells. The in vitro biochemical study demonstrates the phosphorylation of MOB1 by MST2. The phosphorylated MOB1 alone is capable to partially activate NDR1 in vitro, but MST2 is also required for the full activation. The knockdown of MOB1 or MST2 abolishes the OAinduced NDR1 activation in HEK293FT cells. Among MOB1 mutants, in which each serine or threonine residue is replaced with alanine, MOB1 T74A and T181A mutants fail to activate NDR1. Thr74, but not Thr181, is phosphorylated by MST2 in vitro, although MOB1 is also phosphorylated by MST2 at other site(s). The interaction of MOB1 T74A with NDR1 is barely enhanced by OA treatment. These findings indicate that the phosphorylation of MOB1 at Thr74 by MST2 is essential to make a complex of MOB1, MST2 and NDR1, and to fully activate NDR1.

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DrosophilaMob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

Cited by 79 publications

References 42 publications

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

Molecular characterization of human homologs of yeast MOB1

Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1

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