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Mol Biol Cell. 2015 Nov 1;26(21):3867-78. doi: 10.1091/mbc.E15-06-0442. Epub 2015 Sep 2.

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

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
2
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
3
Cancer Genomics Netherlands-Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CX Utrecht, Netherlands.
4
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, NY 10461.
5
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 lauffen@mit.edu fgertler@mit.edu.
6
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 lauffen@mit.edu fgertler@mit.edu.

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(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(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(INV) sensitizes tumor cells to low-growth factor concentrations, thereby increasing the migration and invasion responses that contribute to aggressive, malignant cell phenotypes.

PMID:
26337385
PMCID:
PMC4626070
DOI:
10.1091/mbc.E15-06-0442
[Indexed for MEDLINE]
Free PMC Article

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