Control of Dendritic Cell Migration, T Cell-Dependent Immunity, and Autoimmunity by Protein Tyrosine Phosphatase PTPN12 Expressed in Dendritic Cells

Abstract

f Dendritic cells (DCs) capture and process antigens in peripheral tissues, migrate to lymphoid tissues, and present the antigens to T cells. PTPN12, also known as PTP-PEST, is an intracellular protein tyrosine phosphatase (PTP) involved in cell-cell and cellsubstratum interactions. Herein, we examined the role of PTPN12 in DCs, using a genetically engineered mouse lacking PTPN12 in DCs. Our data indicated that PTPN12 was not necessary for DC differentiation, DC maturation, or cytokine production in response to inflammatory stimuli. However, it was needed for full induction of T cell-dependent immune responses in vivo. This function largely correlated with the need of PTPN12 for DC migration from peripheral sites to secondary lymphoid tissues. Loss of PTPN12 in DCs resulted in hyperphosphorylation of the protein tyrosine kinase Pyk2 and its substrate, the adaptor paxillin. Pharmacological inhibition of Pyk2 or downregulation of Pyk2 expression also compromised DC migration, suggesting that Pyk2 deregulation played a pivotal role in the migration defect caused by PTPN12 deficiency. Together, these findings identified PTPN12 as a key regulator in the ability of DCs to induce antigen-induced T cell responses. This is due primarily to the role of PTPN12 in DC migration from peripheral sites to secondary lymphoid organs through regulation of Pyk2.

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

“…This is in striking contrast to normal cells, in which loss of PTPN12 typically results in reduced migration (5)(6)(7)(8)(9)(10)(11).…”

“…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)(6)(7)(8)(9)(10)(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.…”

PSTPIP2, a Protein Associated with Autoinflammatory Disease, Interacts with Inhibitory Enzymes SHIP1 and Csk

“…2C). Mice deficient in PEP or PTP-PEST do not develop typical signs of autoinflammatory disorder (43)(44)(45)(46), and thus it seems that the major functions of these PTPs are not related to their binding to PSTPIP2. However, if there is a redundancy among the PEST-PTPs that are associated with PSTPIP2, single family member deficiencies would probably not reveal any relevant phenotype.…”

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

“…PTPN12 tyrosine phosphatase was originally identified in a genetic screen for tumor suppressors in triple-negative breast cancers, where it inhibits multiple oncogenic tyrosine kinases, including HER2 and EGFR (49). 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).…”