Regulation of DNA damage responses and cell cycle progression by hMOB2

Gómez, Valentí; Gündoğdu, Ramazan; Gómez, Marta; Hoa, Lily; Panchal, Nilam; O’Driscoll, Mark; Hergovich, Alexander

doi:10.1016/j.cellsig.2014.11.016

Cited by 32 publications

(65 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NDR1/2 kinases may function as the upstream kinases of YAP, which is the main downstream effector of the Hippo signaling pathway (1,(4)(5)(6)(7)12,18). The present study investigated whether MOB2 regulates the activation of NDR1/2 kinases and subsequently modulates the phosphorylation of YAP.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, MOB2 and MOB1 may compete for binding with the same NDR1/2 N-terminal regulatory domain, where MOB1 binds to NDR1/2 to promote the kinase activity of NDR1/2 and MOB2 interacts with NDR1/2 to interfere with the activity of NDR1/2 (4-6). Although MOB2 has been potentially linked to cell cycle progression and the DNA damage response in the context of NDR kinase signaling (1,4,7), the biological role of MOB2 has not yet been fully clarified.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Zhang

Shen

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhang

Shen

et al. 2018

Oncol Lett

View full text Add to dashboard Cite

show abstract

“…According to them, MOB2 is required for ATM-NBS1-SMC1 signalling in DDR, and MOB2 deletion triggers a DNA damage-ATM-CHK2-p53-p21 cascade, which will cause G1/S cell cycle arrest due to accumulated unrepaired DNA damage. Interestingly, NDR kinases can also function in DDR cascade and cell cycle arrest while these two factors seem to function independently in contrast to their tight connections in hippo signalling pathways [1].…”

Section: Editorialmentioning

confidence: 99%

“…Human cells express four related NDR kinases, NDR1, NDR2, LATS1 and LATS2. In Saccharomyces cerevisiae, Dbf2p, Cbk1p, Sid2p and Orb6p are identified as NDR kinases, while in Drosophila melanogaster, Trc and Warts kinases are homologs of human NDR1/2 and LATS1/2 respectively [1].…”

Section: Editorialmentioning

confidence: 99%

See 1 more Smart Citation

MOB Co-activators Associate with NDR/LATS Kinases to Function in DNA Damage Response Signaling and Hippo Pathways

Yang¹

2017

J Cell Signal

View full text Add to dashboard Cite

EditorialSignal transduction cascades link biological reactions with environmental changes, and regulation of the cascades are sophisticated, so various protein kinases are one of the largest superfamilies transcripted by human genome. AGC kinases are a big family of protein kinases playing diverse and crucial roles in cellular activities, such as cell circle and oncogenesis. NDR (nuclear Dbf2-related) kinases and LATS (large tumor suppressor) kinases are important members of AGC kinases family, and are highly conserved from yeast to human beings. Human cells express four related NDR kinases, NDR1, NDR2, LATS1 and LATS2. In Saccharomyces cerevisiae, Dbf2p, Cbk1p, Sid2p and Orb6p are identified as NDR kinases, while in Drosophila melanogaster, Trc and Warts kinases are homologs of human NDR1/2 and LATS1/2 respectively [1].MOB (Mps one binder) proteins are highly conserved in eukaryotes. They perform as signal transducers in intracellular signalling pathways through interactions with NDR/LATS kinases. In budding yeast, MOB1 and MOB2 was found playing central roles in the mitotic exit network (MEN) and cell morphogenesis. In mammals, at least six different MOB proteins are encoded by independent genes, including MOB1A, MOB1B, MOB2, MOB3A, MOB3B and MOB3C. MOB1A/B interacts with NDR/LATS kinases to function in mammalian Hippo signalling, while MOB2 interacts specifically with NDR1/2 kinases to function in DNA damage response and cell circle checkpoint. Both MOB1 and MOB2 can interact with NDR, and their combinations are competitive, with MOB1 upregulating NDR activity and MOB2 downregulating NDR activity [2].Hippo signalling pathway is an ancient and highly conserved protein kinase signalling system controlling basic cellular bioactivities, including cell proliferation, survival and morphogenesis. In these systems, MST/hippo kinases together with MOB coactivators activate AGC kinases NDR/LATS, controlling cell fate and tissue architecture. NDR/LATS kinase-MOB coactivator modules are in the core position of all known hippo pathways [3,4].DNA damage response (DDR) is activated by a cascade of protein kinases that regulate DNA repair in both transcriptional and posttranslational levels. DDR signaling will persist until DNA repair process is completed, during which time cell circle will arrest. According to a large scale screening for DDR factors performed by Stephen J. Elledge in 2011, MOB2 functions as a DDR protein and MOB2 knockdown can cause a cell proliferation defect related to G1/S cell circle arrest [5].Recently Alexander Hergovich performed series biochemistry experiments showing that MOB2 can prevent the accumulation of endogenous DNA damage and a subsequent p53/p21-dependent G1/S cell cycle arrest, while this regulation seems independent of NDR kinases. They also screened for binding partners of MOB2, and they revealed that MOB2 can interact with RAD50 to facilitate the recruitment of MRN (MRE11-RAD50-NBS1) DNA damage sensor complex and activated DDR kinase ATM (Ataxia telangiectasia mutated) to the damaged ...

show abstract

The Effect of TIGAR Knockdown on Apoptotic and Epithelial‐Mesenchymal Markers Expression in Doxorubicin‐Resistant Non‐Small Cell Lung Cancer A549 Cell Lines

Ağca

Kırıcı

Nedzvetsky

et al. 2020

Chemistry & Biodiversity

Self Cite

View full text Add to dashboard Cite

Resistance to chemotherapeutic drugs is a critical problem in cancer therapy, but the underlying mechanism has not been fully elucidated. TP53‐induced glycolysis regulatory phosphatase (TIGAR), an important glycolysis and apoptosis regulator, plays a crucial role in cancer cell survival by protecting cells against oxidative stress‐induced apoptosis. In the present study, we investigated whether TIGAR is involved in epithelial‐mesenchymal transition (EMT) in doxorubicin (DOX)‐resistant human non‐small cell lung cancer (NSCLC), A549/DOX cells. We found that the expression of TIGAR was significantly higher in A549/DOX cells than in the parent A549 cell lines. siRNA‐mediated TIGAR knockdown reduced migration, viability and colony survival of doxorubicin‐resistant lung cancer cells. Also, TIGAR knockdown decreased pro‐survival protein Bcl‐2 and increased pro‐apoptotic Bax and cleaved poly (ADP‐ribose) polymerase (PARP). Moreover, TIGAR depletion significantly up‐regulated both caspase‐3 and caspase‐9 expression. Furthermore, TIGAR depletion up‐regulated the expression of E‐cadherin and down‐regulated the expression of vimentin. These results indicate that TIGAR knockdown may inhibit EMT in doxorubicin (DOX)‐resistant human NSCLC and may represent a therapeutic target for a non‐small lung cancer cells chemoresistance.

show abstract

Regulation of DNA damage responses and cell cycle progression by hMOB2

Cited by 32 publications

References 64 publications

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

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

MOB Co-activators Associate with NDR/LATS Kinases to Function in DNA Damage Response Signaling and Hippo Pathways

The Effect of TIGAR Knockdown on Apoptotic and Epithelial‐Mesenchymal Markers Expression in Doxorubicin‐Resistant Non‐Small Cell Lung Cancer A549 Cell Lines

Contact Info

Product

Resources

About