PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena.
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.
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Shannon K
SK
Hughes
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Madeleine J
MJ
Oudin
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Jenny
J
Tadros
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Jason
J
Neil
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Amanda
A
Del Rosario
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Brian A
BA
Joughin
Cancer Genomics Netherlands-Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CX Utrecht, Netherlands.
Laila
L
Ritsma
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, NY 10461.
Jeff
J
Wyckoff
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Eliza
E
Vasile
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, NY 10461.
Robert
R
Eddy
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Ulrike
U
Philippar
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Alisha
A
Lussiez
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, NY 10461.
John S
JS
Condeelis
Cancer Genomics Netherlands-Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CX Utrecht, Netherlands.
Jacco
J
van Rheenen
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Forest
F
White
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.
Douglas A
DA
Lauffenburger
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.
Frank B
FB
Gertler
D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D003598:Cytoskeletal Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D020033:Protein Isoforms; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000199:Actins; D003598:Cytoskeletal Proteins; C511939:Enah protein, human; D008840:Microfilament Proteins; D020033:Protein Isoforms; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1