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

February 13th, 2015 by Ramesh, M., Krishnan, N., Muthuswamy, S. K., Tonks, N. K.

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.