MenaINV mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis

Directed cell migration, a key process in metastasis, arises from the combined influence of multiple processes, including chemotaxis—the directional movement of cells to soluble cues—and haptotaxis—the migration of cells on gradients of substrate-bound factors. However, it is unclear how chemotactic and haptotactic pathways integrate with each other to drive overall cell behavior. MenaINV has been implicated in metastasis by driving chemotaxis via dysregulation of phosphatase PTP1B and more recently in haptotaxis via interaction with integrin α5β1. Here we find that MenaINV-driven haptotaxis on fibronectin (FN) gradients requires intact signaling between α5β1 integrin and the epidermal growth factor receptor (EGFR), which is influenced by PTP1B. Furthermore, we show that MenaINV-driven haptotaxis and ECM reorganization both require the Rab-coupling protein RCP, which mediates α5β1 and EGFR recycling. Finally, MenaINV promotes synergistic migratory response to combined EGF and FN in vitro and in vivo, leading to hyperinvasive phenotypes. Together our data demonstrate that MenaINV is a shared component of multiple prometastatic pathways that amplifies their combined effects, promoting synergistic cross-talk between RTKs and integrins

MenaINV mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis

Directed cell migration, a key process in metastasis, arises from the combined influence of multiple processes including chemotaxis, the directional movement of cells to soluble cues, and haptotaxis, the migration of cells on gradients of substrate-bound factors. However, it is unclear how chemotactic and haptotactic pathways integrate with each other to drive overall cell behaviour. Mena[superscript INV] has been implicated in metastasis by driving chemotaxis via dysregulation of phosphatase PTP1B, and more recently in haptotaxis via interaction with integrin α5β1. Here we find that Mena[superscript INV]-driven haptotaxis on fibronectin (FN) gradients requires intact signalling between α5β1 integrin and the epidermal growth factor receptor EGFR, which is influenced by PTP1B. Furthermore, we show that Mena[superscript INV]-driven haptotaxis and ECM reorganization both require the Rabcoupling protein RCP, which mediates α5β1 and EGFR recycling. Finally, Mena[superscript INV] promotes synergistic migratory response to combined EGF and FN in vitro and in vivo, leading to hyper-invasive phenotypes. Together, our data demonstrate that Mena[superscript INV] is a shared component of multiple pro-metastatic pathways that amplifies their combined effects, therby promoting synergistic crosstalk between RTKs and integrins.United States. Dept. of Defense. Breast Cancer Research Program (Grant W81XWH-12-1-0031)Massachusetts Institute of Technology. Ludwig Center for Molecular Oncology (Postdoctoral Fellowship)National Institutes of Health (U.S.) (Grant U54- CA112967)Kathy and Curt Marble Cancer Research FundNational Cancer Institute (U.S.) (Grant P30-CA14051