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© Research
Publication : The Journal of cell biology

ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in The Journal of cell biology - 26 Oct 2015

Marchesin V, Castro-Castro A, Lodillinsky C, Castagnino A, Cyrta J, Bonsang-Kitzis H, Fuhrmann L, Irondelle M, Infante E, Montagnac G, Reyal F, Vincent-Salomon A, Chavrier P

Link to Pubmed [PMID] – 26504170

J. Cell Biol. 2015 Oct;211(2):339-58

Invasion of cancer cells into collagen-rich extracellular matrix requires membrane-tethered membrane type 1-matrix metalloproteinase (MT1-MMP) as the key protease for collagen breakdown. Understanding how MT1-MMP is delivered to the surface of tumor cells is essential for cancer cell biology. In this study, we identify ARF6 together with c-Jun NH2-terminal kinase-interacting protein 3 and 4 (JIP3 and JIP4) effectors as critical regulators of this process. Silencing ARF6 or JIP3/JIP4 in breast tumor cells results in MT1-MMP endosome mispositioning and reduces MT1-MMP exocytosis and tumor cell invasion. JIPs are recruited by Wiskott-Aldrich syndrome protein and scar homologue (WASH) on MT1-MMP endosomes on which they recruit dynein-dynactin and kinesin-1. The interaction of plasma membrane ARF6 with endosomal JIPs coordinates dynactin-dynein and kinesin-1 activity in a tug-of-war mechanism, leading to MT1-MMP endosome tubulation and exocytosis. In addition, we find that ARF6, MT1-MMP, and kinesin-1 are up-regulated in high-grade triple-negative breast cancers. These data identify a critical ARF6-JIP-MT1-MMP-dynein-dynactin-kinesin-1 axis promoting an invasive phenotype of breast cancer cells.

http://www.ncbi.nlm.nih.gov/pubmed/26504170