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

Molecular Biology of the Cell
Shannon K HughesFrank B Gertler

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 tumo...Continue Reading

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Citations

Jun 2, 2016·Biochemical and Biophysical Research Communications·William's Elong EdimoChristophe Erneux
Aug 26, 2016·Molecular Biology of the Cell·Madeleine J OudinFrank B Gertler
Nov 9, 2016·Scientific Reports·Maxwell D WeidmannJohn S Condeelis
Nov 29, 2017·Journal of Cell Science·Jeroen BakkerIlana Berlin
Apr 17, 2016·Journal of Cell Science·George S KaragiannisJohn S Condeelis
Jan 8, 2018·Clinical & Experimental Metastasis·George S KaragiannisMaja H Oktay
Feb 6, 2019·Journal of Leukocyte Biology·Luis Rivera SanchezGeorge S Karagiannis
Apr 21, 2017·Cold Spring Harbor Symposia on Quantitative Biology·Madeleine J Oudin, Valerie M Weaver
Nov 5, 2016·Molecular Cancer Therapeutics·Madeleine J OudinFrank B Gertler
May 6, 2021·International Journal of Molecular Sciences·Yuya MonoeKazutake Tsujikawa

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Methods Mentioned

BETA
transgenic
biopsies
xenograft
ELISA
FRET
proximity ligation
xenografts
coimmunoprecipitation
coIP
enzyme-linked immunosorbent assay

Software Mentioned

Mascot
ImageJ

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