title: MenaINV mediates synergistic cross-talk between signaling pathways driving chemotaxis and haptotaxis.
abstract: 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. MenaINVhas 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, MenaINVpromotes synergistic migratory response to combined EGF and FN in vitro and in vivo, leading to hyperinvasive phenotypes. Together our data demonstrate that MenaINVis a shared component of multiple prometastatic pathways that amplifies their combined effects, promoting synergistic cross-talk between RTKs and integrins.
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
authors: Madeleine J
authors: MJ
authors: Oudin
authors: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors: Miles A
authors: MA
authors: Miller
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
authors: Joelle A Z
authors: JA
authors: Klazen
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
authors: Tatsiana
authors: T
authors: Kosciuk
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
authors: Alisha
authors: A
authors: Lussiez
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Shannon K
authors: SK
authors: Hughes
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
authors: Jenny
authors: J
authors: Tadros
authors: Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, Chapel Hill, NC 27514.
authors: James E
authors: JE
authors: Bear
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Douglas A
authors: DA
authors: Lauffenburger
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 fgertler@mit.edu.
authors: Frank B
authors: FB
authors: Gertler
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism* / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D016023:Integrins; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000503:physiopathology; D010750:Phosphoproteins / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D020239:Receptor Cross-Talk; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; C102176:Enah protein, mouse; D039081:Integrin alpha5beta1; D016023:Integrins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1