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J Biol Chem. 2015 Apr 10;290(15):9646-59. doi: 10.1074/jbc.M114.627968. Epub 2015 Feb 13.

A novel phosphatidic acid-protein-tyrosine phosphatase D2 axis is essential for ERBB2 signaling in mammary epithelial cells.

Author information

1
From the Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, the Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, New York 11794, and.
2
From the Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724.
3
From the Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, the Department of Medical Biophysics, Ontario Cancer Institute, Campbell Family Institute for Breast Cancer Research, University of Toronto, Toronto, Canada M5G 2M9.
4
From the Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, tonks@cshl.edu.

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.

KEYWORDS:

Breast Cancer; Cell Signaling; ERBB2; Lipid Signaling; Phosphatidic Acid; Phospholipase D; Phosphotyrosine Signaling; Protein-tyrosine Phosphatase; Receptor-tyrosine Kinase; Signal Transduction

PMID:
25681440
PMCID:
PMC4392266
DOI:
10.1074/jbc.M114.627968
[Indexed for MEDLINE]
Free PMC Article

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