PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena

Shannon K. Hughes, Madeleine J. Oudin, Jenny Tadros, Jason Neil, Amanda Del Rosario, Brian A. Joughin, Laila Ritsma, Jeff Wyckoff, Eliza Vasile, Robert Eddy, Ulrike Philippar, Alisha Lussiez, John S. Condeelis, Jacco Van Rheenen, Forest White, Douglas A. Lauffenburger, Frank B. Gertler

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

During breast cancer progression, alternative mRNA splicing produces functionally distinct isoforms of Mena, an actin regulator with roles in cell migration and metastasis. Aggressive tumor cell subpopulations express MenaINV, which promotes tumor cell invasion by potentiating EGF responses. However, the mechanism by which this occurs is unknown. Here we report that Mena associates constitutively with the tyrosine phosphatase PTP1B and mediates a novel negative feedback mechanism that attenuates receptor tyrosine kinase signaling. On EGF stimulation, complexes containing Mena and PTP1B are recruited to the EGFR, causing receptor dephosphorylation and leading to decreased motility responses. Mena also interacts with the 5′ inositol phosphatase SHIP2, which is important for the recruitment of the Mena-PTP1B complex to the EGFR. When MenaINV is expressed, PTP1B recruitment to the EGFR is impaired, providing a mechanism for growth factor sensitization to EGF, as well as HGF and IGF, and increased resistance to EGFR and Met inhibitors in signaling and motility assays. In sum, we demonstrate that Mena plays an important role in regulating growth factor-induced signaling. Disruption of this attenuation by MenaINV sensitizes tumor cells to low-growth factor concentrations, thereby increasing the migration and invasion responses that contribute to aggressive, malignant cell phenotypes.

Original languageEnglish (US)
Pages (from-to)3867-3878
Number of pages12
JournalMolecular biology of the cell
Volume26
Issue number21
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Hughes, S. K., Oudin, M. J., Tadros, J., Neil, J., Del Rosario, A., Joughin, B. A., Ritsma, L., Wyckoff, J., Vasile, E., Eddy, R., Philippar, U., Lussiez, A., Condeelis, J. S., Van Rheenen, J., White, F., Lauffenburger, D. A., & Gertler, F. B. (2015). PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena. Molecular biology of the cell, 26(21), 3867-3878. https://doi.org/10.1091/mbc.E15-06-0442