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Cancer-associated mutations in the protrusion-targeting region of p190RhoGAP impact tumor cell migration

Authors :
Bertille Montibus
Fabien Binamé
Léo Piquet
Valérie Lagrée
Laure Magnan
Aurélien Bidaud-Meynard
Anne Chabadel
Violaine Moreau
Frédéric Saltel
Source :
The Journal of Cell Biology
Publication Year :
2016
Publisher :
The Rockefeller University Press, 2016.

Abstract

p190RhoGAP (p190A) is a negative regulator of RhoA and localizes to membrane protrusions, where its GAP activity is required for directional migration. Here, Binamé et al. identify the protrusion-localization sequence in p190A and show that cancer-associated mutations in this region affect p190A localization and function as well as tumor cell migration.<br />Spatiotemporal regulation of RhoGTPases such as RhoA is required at the cell leading edge to achieve cell migration. p190RhoGAP (p190A) is the main negative regulator of RhoA and localizes to membrane protrusions, where its GTPase-activating protein (GAP) activity is required for directional migration. In this study, we investigated the molecular processes responsible for p190A targeting to actin protrusions. By analyzing the subcellular localization of truncated versions of p190A in hepatocellular carcinoma cells, we identified a novel functional p190A domain: the protrusion localization sequence (PLS) necessary and sufficient for p190A targeting to leading edges. Interestingly, the PLS is also required for the negative regulation of p190A RhoGAP activity. Further, we show that the F-actin binding protein cortactin binds the PLS and is required for p190A targeting to protrusions. Lastly, we demonstrate that cancer-associated mutations in PLS affect p190A localization and function, as well as tumor cell migration. Altogether, our data unveil a new mechanism of regulation of p190A in migrating tumor cells.

Details

Language :
English
ISSN :
15408140 and 00219525
Volume :
214
Issue :
7
Database :
OpenAIRE
Journal :
The Journal of Cell Biology
Accession number :
edsair.doi.dedup.....de8cec403d82c45060a454e49cdada2b