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

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 f...

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Published in:Journal of experimental & clinical cancer research 2019-04, Vol.38 (1), p.158-158, Article 158
Main Authors: Keller, Maureen, Dubois, Fatéméh, Teulier, Sylvain, Martin, Alexandre P J, Levallet, Jérôme, Maille, Elodie, Brosseau, Solenn, Elie, Nicolas, Hergovich, Alexander, Bergot, Emmanuel, Camonis, Jacques, Zalcman, Gérard, Levallet, Guénaëlle
Format: Article
Language:English
Subjects:
Apoptosis
Cancer
Cancer cells
Cancer genetics
Cancer metastasis
Cell adhesion & migration
Cell culture
Cell cycle
GEF-H1
Gene expression
Genetic aspects
Immunoglobulins
Kinases
Life Sciences
Lung cancer
Metastasis
NDR2 kinase
Phosphatase
Phosphorylation
Proteins
RASSF1A
Stem cells
Tumors
YAP
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Summary: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. 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). 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. 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.
ISSN:1756-9966
0392-9078
1756-9966
DOI:10.1186/s13046-019-1145-8