Rac3 regulates breast cancer invasion and metastasis by controlling adhesion and matrix degradation.

Autor:	Donnelly SK; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY.; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY., Cabrera R; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY., Mao SPH; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY., Christin JR; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY., Wu B; Biophysics and Biophysical Chemistry, School of Medicine, Johns Hopkins University, Baltimore, MD., Guo W; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY., Bravo-Cordero JJ; Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine, Tisch Cancer Institute at Mount Sinai, New York, NY., Condeelis JS; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY.; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY., Segall JE; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY.; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY., Hodgson L; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY louis.hodgson@einstein.yu.edu.; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2017 Dec 04; Vol. 216 (12), pp. 4331-4349. Date of Electronic Publication: 2017 Oct 23.
DOI:	10.1083/jcb.201704048
Abstrakt:	The initial step of metastasis is the local invasion of tumor cells into the surrounding tissue. Invadopodia are actin-based protrusions that mediate the matrix degradation necessary for invasion and metastasis of tumor cells. We demonstrate that Rac3 GTPase is critical for integrating the adhesion of invadopodia to the extracellular matrix (ECM) with their ability to degrade the ECM in breast tumor cells. We identify two pathways at invadopodia important for integrin activation and delivery of matrix metalloproteinases: through the upstream recruiter CIB1 as well as the downstream effector GIT1. Rac3 activity, at and surrounding invadopodia, is controlled by Vav2 and βPIX. These guanine nucleotide exchange factors regulate the spatiotemporal dynamics of Rac3 activity, impacting GIT1 localization. Moreover, the GTPase-activating function of GIT1 toward the vesicular trafficking regulator Arf6 GTPase is required for matrix degradation. Importantly, Rac3 regulates the ability of tumor cells to metastasize in vivo. The Rac3-dependent mechanisms we show in this study are critical for balancing proteolytic activity and adhesive activity to achieve a maximally invasive phenotype. (© 2017 Donnelly et al.)
Databáze:	MEDLINE
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