Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition

Abstract

e PTPN12 is a cytoplasmic protein tyrosine phosphatase (PTP) reported to be a tumor suppressor in breast cancer, through its capacity to dephosphorylate oncogenic receptor protein tyrosine kinases (PTKs), such as ErbB2. However, the precise molecular and cellular impact of PTPN12 deficiency in breast cancer progression remains to be fully clarified. Here, we addressed this issue by examining the effect of PTPN12 deficiency on breast cancer progression in vivo, in a mouse model of ErbB2-dependent breast cancer using a conditional PTPN12-deficient mouse. Our studies showed that lack of PTPN12 in breast epithelial cells accelerated breast cancer development and lung metastases in vivo. PTPN12-deficient breast cancer cells displayed enhanced tyrosine phosphorylation of the adaptor Cas, the adaptor paxillin, and the kinase Pyk2. They exhibited no detectable increase in ErbB2 tyrosine phosphorylation. PTPN12-deficient cells were more resistant to anoikis and had augmented migratory and invasive properties. Enhanced migration was corrected by inhibiting Pyk2. PTPN12-deficient breast cancer cells also acquired partial features of epithelial-to-mesenchymal transition (EMT), a feature of more aggressive forms of breast cancer. Hence, loss of PTPN12 promoted tumor progression in a mouse model of breast cancer, supporting the notion that PTPN12 is a tumor suppressor in human breast cancer. This function was related to the ability of PTPN12 to suppress cell survival, migration, invasiveness, and EMT and to inhibit tyrosine phosphorylation of Cas, Pyk2, and paxillin. These findings enhance our understanding of the role and mechanism of action of PTPN12 in the control of breast cancer progression. P rotein tyrosine phosphatases (PTPs) play a key role in normal cellular processes, such as proliferation, migration, adhesion, differentiation, and immune cell activation (1-3). Depending on the phosphatase and the cell type, they also have the ability either to suppress or to promote malignant transformation (3). PTPN12, also referred to as PTP-PEST (PTP-proline, glutamic acid, serine, and threonine rich), is a cytoplasmic PTP expressed in a wide spectrum of cell types (4). Studies of PTPN12-deficient mice showed that PTPN12 is a critical positive regulator of migration and adhesion in embryonic fibroblasts, endothelial cells, T cells, macrophages, and dendritic cells (5-11). This function relates to the capacity of PTPN12 to dephosphorylate cytoskeletonassociated substrates such as protein tyrosine kinases (PTKs) Pyk2 and FAK or the adaptors Cas, paxillin, and PSTPIP-1. These substrates are components of the cellular machinery controlling migration and adhesion. PTPN12 can also regulate other substrates, including receptor PTKs, such as ErbB2 and the adaptor . Proteomic data suggested that the ability of PTPN12 to regulate Shc might be critical for conversion of Shc-dependent proliferative signals into migratory signals (15). Several PTPN12 substrates, and in particular, Cas, paxillin, and Shc, also directly associate with PTPN12....

Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma

“…In addition, studies of Ptpn12-deficient mice have shown that Ptpn12 regulates the migration of endothelial cells, dendritic cells, and macrophages, probably through dephosphorylation of Prk2, FAK, Cas, and paxillin (50)(51)(52). These antimigratory functions of PTPN12 also have been observed in several types of human cancers, including breast, ovary, and prostate cancers (53)(54)(55). Consistent with this, Ptpn12 was inactivated in our IHBC/SB-derived tumors by transposon insertion.…”

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

“…In this study, we propose that PTPN12 plays a key role in CD99-mediated negative regulation of ␤1 integrin activity and tumor progression. This assumption is consistent with recent reports showing that PTPN12 functions as a tumor suppressor (67)(68)(69). Taken together, our results suggest that CD99-derived agonist ligands have potential as novel therapeutic reagents to suppress tumor progression via negative regulation of ␤1 integrin activity.…”

“…However, SHP2 suppresses the development of hepatocellular carcinoma by suppressing inflammatory signaling through the STAT3 pathway (65). Likewise, our results show that SHP2 activates the tumor suppressor PTPN12 through ERK signaling, suggesting a tumor-suppressive role for SHP2 through the CD99 signaling axis (66)(67)(68). The influence of the cellular context and tumor microenvironment on the regulation of SHP2's role in tumor progression remains unclear.…”

Tumor suppressor DAPK1 catalyzes Adhesion Assembly on Rigid but Anoikis on Soft Matrices

“…There was reason to believe that DAPK1 assembly into the adhesions was a normal part of the cell-matrix interaction and that a phosphatase was needed to disassemble adhesions on soft surfaces and to activate DAPK1. A major tyrosine phosphatase that was implicated in cancer and motility was PTPN12 (29,30). To test for its possible involvement, we added an inhibitor of PTPN12 and found that it blocked DAPK1 apoptotic function in MEFs.…”