A Novel Phosphatidic Acid-Protein Tyrosine Phosphatase D2 Axis is Essential for ERBB2 Signaling in Mammary Epithelial Cells

Ramesh, M., Krishnan, N., Muthuswamy, S. K., Tonks, N. K. (2015) A Novel Phosphatidic Acid-Protein Tyrosine Phosphatase D2 Axis is Essential for ERBB2 Signaling in Mammary Epithelial Cells. Journal of Biological Chemistry, 290 (15). pp. 9646-9659. ISSN 0021-9258

URL: http://www.ncbi.nlm.nih.gov/pubmed/25681440
DOI: 10.1074/jbc.M114.627968

Abstract

We used a loss-of-function screen to investigate the role of classical Protein Tyrosine Phosphatases (PTPs) in three-dimensional mammary epithelial cell morphogenesis and ERBB2 signaling. The study revealed a novel role for PTPD2 as a positive regulator of ERBB2 signaling. Suppression of PTPD2 attenuated the ERBB2-induced multiacinar phenotype in three-dimensional cultures specifically by inhibiting ERBB2-mediated loss of polarity and lumen filling. In contrast, overexpression of PTPD2 enhanced the ERBB2 phenotype. We also found that a lipid second messenger, phosphatidic acid, bound PTPD2 in vitro and enhanced its catalytic activity. Small-molecule inhibitors of Phospholipase D (PLD), an enzyme that produces phosphatidic acid in cells, also attenuated the ERBB2 phenotype. Exogenously added phosphatidic acid rescued the PLD-inhibition phenotype, but only when PTPD2 was present. These findings illustrate a novel pathway involving PTPD2 and the lipid second messenger phosphatidic acid that promotes ERBB2 function.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > ErbB
diseases & disorders > cancer > cancer types > breast cancer
organs, tissues, organelles, cell types and functions > tissues types and functions > signal transduction
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL labs > Muthuswamy lab
CSHL labs > Tonks lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date Deposited: 22 Apr 2015 19:11
Last Modified: 16 Oct 2015 15:06
PMCID: PMC4392266
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31347

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