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 J. Eddy, Ulrike Philippar, Alisha Lussiez, John S. Condeelis, Jacco Van Rheenen, Forest White, Douglas A. Lauffenburger, Frank B. Gertler

Research output: Contribution to journalArticle

19 Citations (Scopus)

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

Fingerprint

Microfilament Proteins
Receptor Protein-Tyrosine Kinases
Epidermal Growth Factor
Intercellular Signaling Peptides and Proteins
Neoplasms
Alternative Splicing
Phosphoric Monoester Hydrolases
Cell Movement
Tyrosine
Actins
Protein Isoforms
Breast Neoplasms
Neoplasm Metastasis
Phenotype
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Hughes, S. K., Oudin, M. J., Tadros, J., Neil, J., Del Rosario, A., Joughin, B. 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

PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena. / Hughes, Shannon K.; Oudin, Madeleine J.; Tadros, Jenny; Neil, Jason; Del Rosario, Amanda; Joughin, Brian A.; Ritsma, Laila; Wyckoff, Jeff; Vasile, Eliza; Eddy, Robert J.; Philippar, Ulrike; Lussiez, Alisha; Condeelis, John S.; Van Rheenen, Jacco; White, Forest; Lauffenburger, Douglas A.; Gertler, Frank B.

In: Molecular Biology of the Cell, Vol. 26, No. 21, 01.11.2015, p. 3867-3878.

Research output: Contribution to journalArticle

Hughes, SK, Oudin, MJ, Tadros, J, Neil, J, Del Rosario, A, Joughin, BA, Ritsma, L, Wyckoff, J, Vasile, E, Eddy, RJ, Philippar, U, Lussiez, A, Condeelis, JS, Van Rheenen, J, White, F, Lauffenburger, DA & Gertler, FB 2015, 'PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena', Molecular Biology of the Cell, vol. 26, no. 21, pp. 3867-3878. https://doi.org/10.1091/mbc.E15-06-0442
Hughes, Shannon K. ; Oudin, Madeleine J. ; Tadros, Jenny ; Neil, Jason ; Del Rosario, Amanda ; Joughin, Brian A. ; Ritsma, Laila ; Wyckoff, Jeff ; Vasile, Eliza ; Eddy, Robert J. ; Philippar, Ulrike ; Lussiez, Alisha ; Condeelis, John S. ; Van Rheenen, Jacco ; White, Forest ; Lauffenburger, Douglas A. ; Gertler, Frank B. / PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena. In: Molecular Biology of the Cell. 2015 ; Vol. 26, No. 21. pp. 3867-3878.
@article{03aefe5c0a6b492b95336e3fc1b5335c,
title = "PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena",
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.",
author = "Hughes, {Shannon K.} and Oudin, {Madeleine J.} and Jenny Tadros and Jason Neil and {Del Rosario}, Amanda and Joughin, {Brian A.} and Laila Ritsma and Jeff Wyckoff and Eliza Vasile and Eddy, {Robert J.} and Ulrike Philippar and Alisha Lussiez and Condeelis, {John S.} and {Van Rheenen}, Jacco and Forest White and Lauffenburger, {Douglas A.} and Gertler, {Frank B.}",
year = "2015",
month = "11",
day = "1",
doi = "10.1091/mbc.E15-06-0442",
language = "English (US)",
volume = "26",
pages = "3867--3878",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "21",

}

TY - JOUR

T1 - PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena

AU - Hughes, Shannon K.

AU - Oudin, Madeleine J.

AU - Tadros, Jenny

AU - Neil, Jason

AU - Del Rosario, Amanda

AU - Joughin, Brian A.

AU - Ritsma, Laila

AU - Wyckoff, Jeff

AU - Vasile, Eliza

AU - Eddy, Robert J.

AU - Philippar, Ulrike

AU - Lussiez, Alisha

AU - Condeelis, John S.

AU - Van Rheenen, Jacco

AU - White, Forest

AU - Lauffenburger, Douglas A.

AU - Gertler, Frank B.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84945950866&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84945950866&partnerID=8YFLogxK

U2 - 10.1091/mbc.E15-06-0442

DO - 10.1091/mbc.E15-06-0442

M3 - Article

VL - 26

SP - 3867

EP - 3878

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 21

ER -