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

• Published in: Molecular biology of the cell Vol. 27; no. 20; pp. 3085 - 3094
• Main Authors: Oudin, Madeleine J, Miller, Miles A, Klazen, Joelle A Z, Kosciuk, Tatsiana, Lussiez, Alisha, Hughes, Shannon K, Tadros, Jenny, Bear, James E, Lauffenburger, Douglas A, Gertler, Frank B
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 15.10.2016
• Subjects: Animals; Cell Adhesion Molecules - metabolism; Cell Movement - physiology; Chemotaxis - physiology; Cytoskeletal Proteins - metabolism; Cytoskeletal Proteins - physiology; Integrin alpha5beta1 - metabolism; Integrins; Mice; Microfilament Proteins - metabolism; Neoplasm Metastasis - physiopathology; Phosphoproteins - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Receptor Cross-Talk; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction - physiology; Tumor Cells, Cultured
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.e16-04-0212

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. Mena 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 -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 Mena -driven haptotaxis and ECM reorganization both require the Rab-coupling protein RCP, which mediates α5β1 and EGFR recycling. Finally, Mena promotes synergistic migratory response to combined EGF and FN in vitro and in vivo, leading to hyperinvasive phenotypes. Together our data demonstrate that Mena is a shared component of multiple prometastatic pathways that amplifies their combined effects, promoting synergistic cross-talk between RTKs and integrins.