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

Sara K. Donnelly, Ramon Cabrera, Serena P.H. Mao, John R. Christin, Bin Wu, Wenjun Guo, Jose Javier Bravo-Cordero, John S. Condeelis, Jeffrey E. Segall, Louis Hodgson

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The initial step of metastasis is the local invasion of tumor cells into the surrounding tissue. Invadopodia are actinbased 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.

Original languageEnglish (US)
Pages (from-to)4331-4349
Number of pages19
JournalJournal of Cell Biology
Volume216
Issue number12
DOIs
StatePublished - Jan 1 2017

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GTP Phosphohydrolases
Breast Neoplasms
Neoplasm Metastasis
Extracellular Matrix
Guanine Nucleotide Exchange Factors
Neoplasms
Matrix Metalloproteinases
Integrins
Adhesives
Phenotype
Podosomes

ASJC Scopus subject areas

  • Cell Biology

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Rac3 regulates breast cancer invasion and metastasis by controlling adhesion and matrix degradation. / Donnelly, Sara K.; Cabrera, Ramon; Mao, Serena P.H.; Christin, John R.; Wu, Bin; Guo, Wenjun; Bravo-Cordero, Jose Javier; Condeelis, John S.; Segall, Jeffrey E.; Hodgson, Louis.

In: Journal of Cell Biology, Vol. 216, No. 12, 01.01.2017, p. 4331-4349.

Research output: Contribution to journalArticle

Donnelly, Sara K. ; Cabrera, Ramon ; Mao, Serena P.H. ; Christin, John R. ; Wu, Bin ; Guo, Wenjun ; Bravo-Cordero, Jose Javier ; Condeelis, John S. ; Segall, Jeffrey E. ; Hodgson, Louis. / Rac3 regulates breast cancer invasion and metastasis by controlling adhesion and matrix degradation. In: Journal of Cell Biology. 2017 ; Vol. 216, No. 12. pp. 4331-4349.
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