Hippo Signaling in Mitosis: An Updated View in Light of the MEN Pathway

Hergovich, Alexander

doi:10.1007/978-1-4939-6502-1_19

Cited by 12 publications

(15 citation statements)

References 96 publications

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“…In agreement with the role of Hippo in cell cycle progression and specifically in the mitotic phase, we found that several genes related to cytokinesis and mitotic spindle organization were differentially expressed in the hippo (RNAi) RNA sequencing analysis (RNAseq) ( S1 Table ). Importantly, these included genes already known to be regulated by Mst1/2 or Lats1/2 and mainly involved in spindle orientation ( afadin, Drosophila discs large, polo-like kinase 1 ) [ 38 – 40 ] ( S1 Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Our findings demonstrate that in planarians, Hippo is essential for proper cell cycle progression and, specifically, for successful completion of mitosis. The role of core Hippo signaling elements in critical mitotic events, namely in centrosomal duplication, chromosomal alignment, spindle formation, and completion of cytokinesis, has also been reported in Drosophila and vertebrate species [ 36 , 40 , 50 – 53 ]. Planarian hippo (RNAi) cells showed improper assembly of the mitotic spindle.…”

Section: Discussionmentioning

confidence: 99%

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Hippo signaling controls cell cycle and restricts cell plasticity in planarians

et al. 2018

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The Hippo pathway plays a key role in regulating cell turnover in adult tissues, and abnormalities in this pathway are consistently associated with human cancers. Hippo was initially implicated in the control of cell proliferation and death, and its inhibition is linked to the expansion of stem cells and progenitors, leading to larger organ size and tumor formation. To understand the mechanism by which Hippo directs cell renewal and promotes stemness, we studied its function in planarians. These stem cell–based organisms are ideal models for the analysis of the complex cellular events underlying tissue renewal in the whole organism. hippo RNA interference (RNAi) in planarians decreased apoptotic cell death, induced cell cycle arrest, and could promote the dedifferentiation of postmitotic cells. hippo RNAi resulted in extensive undifferentiated areas and overgrowths, with no effect on body size or cell number. We propose an essential role for hippo in controlling cell cycle, restricting cell plasticity, and thereby preventing tumoral transformation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hippo signaling controls cell cycle and restricts cell plasticity in planarians

et al. 2018

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“…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. Given that loss of hMOB2 can trigger a p53-dependent G1/S cell cycle arrest [37] and that NDR/LATS are associated with cell cycle progression [20,21], it will certainly be necessary to re-examine these HCC-based hMOB2 knockout cells to ensure the changes in NDR1/2, LATS1/2, and hMOB1 phosphorylation upon hMOB2 loss [62] are not merely reflecting indirect effects triggered by an underlying cell cycle arrest/delay.…”

Section: An Overview Of Mobs and The Hippo Pathwaymentioning

confidence: 99%

“…Since we are only briefly summarising here the mitotic functions of hMOB1, for a detailed overview of the cell cycle roles of hMOB1 see refs. [20,21]. Initially, a kinase-targeting RNAi screen found that the NDR1 kinase, a binding partner of hMOB1 and hMOB2 [1], is possibly involved in regulating spindle orientation [103].…”

Section: Cancer-associated Cellular Functions Of Mobsmentioning

confidence: 99%

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

Gündoğdu

Hergovich

2019

Cells

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The family of MOBs (monopolar spindle-one-binder proteins) is highly conserved in the eukaryotic kingdom. MOBs represent globular scaffold proteins without any known enzymatic activities. They can act as signal transducers in essential intracellular pathways. MOBs have diverse cancer-associated cellular functions through regulatory interactions with members of the NDR/LATS kinase family. By forming additional complexes with serine/threonine protein kinases of the germinal centre kinase families, other enzymes and scaffolding factors, MOBs appear to be linked to an even broader disease spectrum. Here, we review our current understanding of this emerging protein family, with emphases on post-translational modifications, protein-protein interactions, and cellular processes that are possibly linked to cancer and other diseases. In particular, we summarise the roles of MOBs as core components of the Hippo tissue growth and regeneration pathway.

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“…We provide evidence for a NDR2/GEF-H1 interaction, leading to GEF-H1 Ser885 phosphorylation/inactivation, followed by RhoB down-regulation. Given the involvement of GEF-H1 and NDR kinases in cell cycle [10, 11], we investigated cell cycle alterations in RASSF1A-depleted HBEC. We found that RASSF1A knockdown induced mitotic abscission defects, which were reverted upon GEF-H1 overexpression or NDR1/2 depletion.…”

Section: Introductionmentioning

confidence: 99%

NDR2 kinase contributes to cell invasion and cytokinesis defects induced by the inactivation of RASSF1A tumor-suppressor gene in lung cancer cells

Keller

Dubois

Teulier

et al. 2019

J Exp Clin Cancer Res

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Background RASSF1A, a tumor suppressor gene, is frequently inactivated in lung cancer leading to a YAP-dependent epithelial-mesenchymal transition (EMT). Such effects are partly due to the inactivation of the anti-migratory RhoB GTPase via the inhibitory phosphorylation of GEF-H1, the GDP/GTP exchange factor for RhoB. However, the kinase responsible for RhoB/GEF-H1 inactivation in RASSF1A-depleted cells remained unknown. Methods NDR1/2 inactivation by siRNA or shRNA effects on epithelial-mesenchymal transition, invasion, xenograft formation and growth in SCID−/− Beige mice, apoptosis, proliferation, cytokinesis, YAP/TAZ activation were investigated upon RASSF1A loss in human bronchial epithelial cells (HBEC). Results We demonstrate here that depletion of the YAP-kinases NDR1/2 reverts migration and metastatic properties upon RASSF1A loss in HBEC. We show that NDR2 interacts directly with GEF-H1 (which contains the NDR phosphorylation consensus motif HXRXXS/T), leading to GEF-H1 phosphorylation. We further report that the RASSF1A/NDR2/GEF-H1/RhoB/YAP axis is involved in proper cytokinesis in human bronchial cells, since chromosome proper segregation are NDR-dependent upon RASSF1A or GEF-H1 loss in HBEC. Conclusion To summarize, our data support a model in which, upon RASSF1A silencing, NDR2 gets activated, phosphorylates and inactivates GEF-H1, leading to RhoB inactivation. This cascade induced by RASSF1A loss in bronchial cells is responsible for metastasis properties, YAP activation and cytokinesis defects. Electronic supplementary material The online version of this article (10.1186/s13046-019-1145-8) contains supplementary material, which is available to authorized users.

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Hippo Signaling in Mitosis: An Updated View in Light of the MEN Pathway

Cited by 12 publications

References 96 publications

Hippo signaling controls cell cycle and restricts cell plasticity in planarians

Hippo signaling controls cell cycle and restricts cell plasticity in planarians

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

NDR2 kinase contributes to cell invasion and cytokinesis defects induced by the inactivation of RASSF1A tumor-suppressor gene in lung cancer cells

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