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

作者：Marchesin Valentina; Castro Castro Antonio; Lodillinsky Catalina; Castagnino Alessia; Cyrta Joanna; Bonsang Kitzis Helene; Fuhrmann Laetitia; Irondelle Marie; Infante Elvira; Montagnac Guillaume; Reyal Fabien; Vincent Salomon Anne; Chavrier Philippe^*

来源：The Journal of Cell Biology, 2015, 211(2): 339-358.

DOI：10.1083/jcb.201506002

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 activiiy 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.

• 出版日期2015-10-26