Investigating the Mechanism of Mena(INV)-Driven Metastasis
Abstract
Mena, an actin regulatory protein, is upregulated in human breast cancer and is alternatively spliced to produce protein isoforms with distinct functions during tumor progression. The invasion-specific MenaINV isoform, which is upregulated in invasive and motile cells, increases metastasis by potentiating tumor cell responses to EGF via dysregulation of the tyrosine phosphatase PTP1B. We show that expression of MenaINV sensitized responses to other EGFR ligands as well as two other growth factors associated with tumor progression, HGF and IGF, whose receptors are known PTP1B substrates. MenaINV can also drive invasion by affecting signalling downstream of integrins and via its direct interaction with 5 1. In 3D invasion assays, addition of fibronectin to a collagen gel drove invasion of MenaINV-expressing cells in the absence of any growth factor ligand, an effect which was driven by its interaction with 5 and dependent on signalling via EGFR and Met. Furthermore, addition of fibronectin caused an even greater potentiation of EGF-induced invasion by MenaINV, an effect which was dependent upon its interaction with 5. Overall, these results suggest that the pro-metastatic effects of MenaINV involve its ability to bind 5 and regulate bidirectional signaling with FN and growth factors in the tumor microenvironment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2013
- Accession Number
- ADA598725
Entities
People
- Betty Diamond
- Madeleine J. Oudin
Organizations
- Massachusetts Institute of Technology