A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination

作者：Frittoli Emanuela; Palamidessi Andrea; Marighetti Paola; Confalonieri Stefano; Bianchi Fabrizio; Malinvemo Chiara; Mazzarol Giovanni; Viale Giuseppe; Martin Padura Ines; Garre Massimilliano; Parazzoli Dario; Mattei Valentina; Cortellino Salvatore; Bertalot Giovanni; Di Fiore Pier Paolo^*; Scita Giorgio

来源：The Journal of Cell Biology, 2014, 206(2): 307-328.

DOI：10.1083/jcb.201403127

The mechanisms by which tumor cells metastasize and the role of endocytic proteins in this process are not well understood. We report that overexpression of the GTPase RAB5A, a master regulator of endocytosis, is predictive of aggressive behavior and metastatic ability in human breast cancers. RAB5A is necessary and sufficient to promote local invasion and distant dissemination of various mammary and nonmammary tumor cell lines, and this prometastatic behavior is associated with increased intratumoral cell motility. Specifically, RAB5A is necessary for the formation of invadosomes, membrane protrusions specialized in extracellular matrix (ECM) degradation. RAB5A promotes RAB4- and RABENOSYN-5-dependent endo/exocytic cycles (EECs) of critical cargos (membrane-type 1 matrix metalloprotease [MT1-MMP and beta 3 integrin) required for invadosome formation in response to motogenic stimuli. This trafficking circuitry is necessary for spatially localized hepatocyte growth factor (HGF)/MET signaling that drives invasive, proteolysis-dependent chemotaxis in vitro and for conversion of ductal carcinoma in situ to invasive ductal carcinoma in vivo. Thus, RAB5A/RAB4 EECs promote tumor dissemination by controlling a proteolytic, mesenchymal invasive program.

• 出版日期2014-7-21