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Mol Biol Cell. 2016 Oct 15;27(20):3085-3094. Epub 2016 Aug 24.

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

Author information

1
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142.
2
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.
3
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.
4
Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, Chapel Hill, NC 27514.
5
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.

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. 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.

PMID:
27559126
PMCID:
PMC5063616
DOI:
10.1091/mbc.E16-04-0212
[Indexed for MEDLINE]
Free PMC Article

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