PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena
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Author(s)
Hughes, Shannon Kay
Oudin, Madeleine Julie
Tadros, Jenny
Neil, Jason Robert
Del Rosario, Amanda M.
Joughin, Brian A.
Ritsma, Laila
Wyckoff, Jeff
Vasile, Eliza
Eddy, Robert
Date Issued
September 2015
Journal
Molecular Biology of the Cell
Publisher
American Society for Cell Biology
Citation
Hughes, S. K., M. J. Oudin, J. Tadros, J. Neil, A. Del Rosario, B. A. Joughin, L. Ritsma, et al. “PTP1B-Dependent Regulation of Receptor Tyrosine Kinase Signaling by the Actin-Binding Protein Mena.” Molecular Biology of the Cell 26, no. 21 (September 2, 2015): 3867–3878.
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Author's final manuscript
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 Mena[superscript INV], 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 Mena[superscript INV] 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 Mena[superscript INV] sensitizes tumor cells to low–growth factor concentrations, thereby increasing the migration and invasion responses that contribute to aggressive, malignant cell phenotypes.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1091/mbc.E15-06-0442
