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J Biol Chem. 2016 Feb 26;291(9):4323-33. doi: 10.1074/jbc.M115.695940. Epub 2016 Jan 6.

Rapid Remodeling of Invadosomes by Gi-coupled Receptors: DISSECTING THE ROLE OF Rho GTPases.

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From the Division of Cell Biology and.
the Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, Connecticut 06030, and.
the Department of Cell Biology, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands.
Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
From the Division of Cell Biology and


Invadosomes are actin-rich membrane protrusions that degrade the extracellular matrix to drive tumor cell invasion. Key players in invadosome formation are c-Src and Rho family GTPases. Invadosomes can reassemble into circular rosette-like superstructures, but the underlying signaling mechanisms remain obscure. Here we show that Src-induced invadosomes in human melanoma cells (A375M and MDA-MB-435) undergo rapid remodeling into dynamic extracellular matrix-degrading rosettes by distinct G protein-coupled receptor agonists, notably lysophosphatidic acid (LPA; acting through the LPA1 receptor) and endothelin. Agonist-induced rosette formation is blocked by pertussis toxin, dependent on PI3K activity and accompanied by localized production of phosphatidylinositol 3,4,5-trisphosphate, whereas MAPK and Ca(2+) signaling are dispensable. Using FRET-based biosensors, we show that LPA and endothelin transiently activate Cdc42 through Gi, concurrent with a biphasic decrease in Rac activity and differential effects on RhoA. Cdc42 activity is essential for rosette formation, whereas G12/13-mediated RhoA-ROCK signaling suppresses the remodeling process. Our results reveal a Gi-mediated Cdc42 signaling axis by which G protein-coupled receptors trigger invadosome remodeling, the degree of which is dictated by the Cdc42-RhoA activity balance.


CDC42; G protein-coupled receptor (GPCR); Rac (Rac GTPase); Rho (Rho GTPase); biosensor; calcium intracellular release; fluorescence resonance energy transfer (FRET); imaging; invadopodia; phosphatidylinositide 3-kinase (PI 3-kinase)

[Available on 2017-02-26]
[Indexed for MEDLINE]
Free PMC Article

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