PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review

Abstract

PTPN2 (protein tyrosine phosphatase non-receptor 2), also called TCPTP (T cell protein tyrosine phosphatase), is a member of the PTP family signaling proteins. Phosphotyrosine-based signaling of this non-transmembrane protein is essential for regulating cell growth, development, differentiation, survival, and migration. In particular, PTPN2 received researchers' attention when Manguso et al. identified PTPN2 as a cancer immunotherapy target using in vivo CRISPR library screening. In this review, we attempt to summarize the important functions of PTPN2 in terms of its structural and functional properties, inflammatory reactions, immunomodulatory properties, and tumor immunity. PTPN2 exerts synergistic anti-inflammatory effects in various inflammatory cells and regulates the developmental differentiation of immune cells. The diversity of PTPN2 effects in different types of tumors makes it a potential target for tumor immunotherapy.

Keywords: PTPN2; inflammation; tumor immunotherapy.

Figure 1

Structure of 45 kD and 48 kD PTPN2 variants. This image indicates the catalytic and non-catalytic C-terminal domains of PTPN2. Its catalytic domain highlights the high degree of primary sequence conservation. The DNA binding domain contains two basic clusters (residues 350–358 (RKRIREDRK) and 377–381 (RKRKR)) that form a bipartite nuclear localization signal (NLS). TC45 localizes to the nucleus by virtue of NLS. The hydrophobic C-terminal tail of TC48 must override the bipartite NLS to permit the targeting of the ER. The region shown in blue (from 350–415) is where sites in TC48 interact with p23 and p25.

Figure 2

Various mechanisms of PTPN2 in different kinds of cells. Abnormal expression of PTPN2 in epithelial cells will result in many diseases through different mechanisms, such as p-STAT1/claudin-2 in inflammatory bowel, p38/NF-κB in renal cell damage, and JAK/STAT in diabetic periodontitis. The antibody of PTPN2 in APOE^−/− mice inhibits atherosclerosis through diminishing p65/p38/STAT3 signaling pathway. What’s more, PTPN2 influences T cell function, including cell proliferation and IFN-γ production, through JAK/STAT signaling pathway.