Activation of Src by Protein Tyrosine Phosphatase 1B Is Required for ErbB2 Transformation of Human Breast Epithelial Cells

Abstract

Protein tyrosine phosphatase (PTP) 1B plays a major role in inhibiting signaling from the insulin and leptin receptors. Recently, PTP1B was found to have an unexpected positive role in ErbB2 signaling in a mouse model of breast cancer, but the mechanism underlying this effect has been unclear. Using human breast epithelial cells grown in a three-dimensional matrix, we found that PTP1B, but not the closely related enzyme T-cell PTP, is required for ErbB2 transformation in vitro. Activation of ErbB2, but not ErbB1, increases PTP1B expression, and increased expression of PTP1B activates Src and induces a Src-dependent transformed phenotype. These findings identify a molecular mechanism by which PTP1B links an important oncogenic receptor tyrosine kinase to signaling pathways that promote aberrant cell division and survival in human breast epithelial cells. [Cancer Res 2009;69(11):4582-8]

Protein-tyrosine Phosphatase 1B Antagonized Signaling by Insulin-like Growth Factor-1 Receptor and Kinase BRK/PTK6 in Ovarian Cancer Cells*

“…In contrast, PTP1B is highly expressed in some tumors, such as breast, and plays a positive role in signaling by the HER2 oncoprotein-tyrosine kinase. Although the mechanism is unclear and may involve dephosphorylation and activation of SRC (52) or activation of RAS-MAPK signaling via dephosphorylation of p62DOK (53), this raises the possibility that PTP1B may also be a therapeutic target for treatment of HER2-positive cancer (54). Nevertheless, consistent with the importance of context and specificity in PTP function, signaling through the EGF receptor, which is from the same family of PTKs as HER2, is not augmented by PTP1B; in fact, PTP1B is recognized for its inhibitory effects on EGFR signaling (23).…”

Protein tyrosine phosphatase PTP1B in cell adhesion and migration

“…17 Src activation by PTP1B was further demonstrated in several different cell models. 3,4,12,18,[45][46][47] Using a combination of time lapse, total internal reflection fluorescence microscopy, and BiFC we were able to visualize ER-bound PTP1B/ Src complexes as small fluorescent puncta distributed uniformly at the plasma membrane in contact with the substrate. 8 The substrate trap mutation (D181A) in PTP1B and the tyrosine 529 at the C-tail of Src were both required for BiFC to occur, as well as the plasma membrane targeting motif of Src.…”

Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the ‘PTP-ome'

“…The offspring that result from a cross between transgenic mice that express an oncogenically activated form of ERBB2 in mammary glands and mice with targeted deletion of the PTP1B gene display delayed and attenuated tumor development and lung metastasis (Bentires-Alj and Neel 2007;Julien et al 2007). Moreover, in an in vitro model of breast cancer, the formation of multiacinar structures following activation of ERBB2 requires expression of PTP1B (Arias-Romero et al 2009). These results implicate PTP1B as a positive regulator of the development and metastasis of ERBB2-positive breast tumors (Tonks and Muthuswamy 2007).…”