PTPN2

Official Full Name

protein tyrosine phosphatase non-receptor type 2

Organism

Homo sapiens

GeneID

5771

Background

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. Members of the PTP family share a highly conserved catalytic motif, which is essential for the catalytic activity. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Epidermal growth factor receptor and the adaptor protein Shc were reported to be substrates of this PTP, which suggested the roles in growth factor mediated cell signaling. Multiple alternatively spliced transcript variants encoding different isoforms have been found. Two highly related but distinctly processed pseudogenes that localize to chromosomes 1 and 13, respectively, have been reported. [provided by RefSeq, May 2011]

Synonyms

PTN2; PTPT; TC45; TC48; TCPTP; TC-PTP; TCELLPTP;

Protein Sequence

MPTTIEREFEELDTQRRWQPLYLEIRNESHDYPHRVAKFPENRNRNRYRDVSPYDHSRVKLQNAENDYINASLVDIEEAQRSYILTQGPLPNTCCHFWLMVWQQKTKAVVMLNRIVEKESVKCAQYWPTDDQEMLFKETGFSVKLLSEDVKSYYTVHLLQLENINSGETRTISHFHYTTWPDFGVPESPASFLNFLFKVRESGSLNPDHGPAVIHCSAGIGRSGTFSLVDTCLVLMEKGDDINIKQVLLNMRKYRMGLIQTPDQLRFSYMAIIEGAKCIKGDSSIQKRWKELSKEDLSPAFDHSPNKIMTEKYNGNRIGLEEEKLTGDRCTGLSSKMQDTMEENSESALRKRIREDRKATTAQKVQQMKQRLNENERKRKRWLYWQPILTKMGFMSVILVGAFVGWTLFFQQNAL

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The PTPN2 (Protein Tyrosine Phosphatase Non-Receptor Type 2) gene is located on human chromosome 18p11.21 p11.22 and encodes a non-receptor type protein tyrosine phosphatase known as T-cell protein tyrosine phosphatase (TC-PTP). Two major isoforms are expressed: the full-length TC45 (45 kDa), which predominantly localizes to the nucleus, and the shorter TC48 (48 kDa), which is anchored to the endoplasmic reticulum (ER) membrane through a C-terminal hydrophobic domain. This distinct subcellular distribution allows PTPN2 to regulate signaling events in different compartments. Structurally, PTPN2 contains a conserved catalytic domain whose activity depends on the precise positioning of the WPD loop and P-loop motifs, as well as a regulatory nuclear localization signal. Unlike SHP-2 encoded by PTPN11, PTPN2 lacks SH2 domains and instead recognizes phosphotyrosine residues directly through its catalytic domain, enabling selective dephosphorylation of diverse signaling proteins.

Figure 1. Structure of 45 kD and 48 kD PTPN2 variants. Figure 1. Structure of 45 kD and 48 kD PTPN2 variants. (Song J, et al., 2022)

Physiological Roles in Immune Regulation

PTPN2 plays a central role in fine-tuning immune signaling pathways. In cytokine signaling, it directly dephosphorylates JAK1, JAK3, STAT1, STAT3, and STAT6, thereby attenuating pathways triggered by interleukins such as IL-2, IL-6, and IL-4, as well as interferon-mediated responses. In T cells, PTPN2 modulates activation thresholds and differentiation by targeting TCR-associated signaling proteins, including FYB and LCK. Beyond immune signaling, PTPN2 also regulates growth factor receptor signaling by dephosphorylating EGFR, INSR, and CSF1R, thereby suppressing downstream pathways. This broad substrate specificity highlights its importance as a negative regulator of immune homeostasis and cell growth.

Figure 2. Negative regulation of the JAK–STAT pathway. Figure 2. Negative regulation of the JAK–STAT pathway. (Shuai K, et al., 2003)

Roles in Metabolic Regulation

PTPN2 contributes to glucose homeostasis through dual mechanisms. First, it directly dephosphorylates the insulin receptor, reducing insulin signaling. Second, it suppresses IL-6 signaling in hepatocytes, thereby decreasing hepatic glucose production. These functions position PTPN2 as a critical molecular node linking immune responses with metabolic regulation. Furthermore, PTPN2 can interact with integrins, particularly α1β1, where it is recruited to the plasma membrane upon integrin activation to negatively regulate EGF signaling. This mechanism contributes to anchorage-dependent growth inhibition.

PTPN2 in Tumorigenesis and Immune Regulation

PTPN2 functions as a tumor suppressor in multiple cancer types, and its loss of function is closely associated with tumor development. In T-cell acute lymphoblastic leukemia (T-ALL), deletions or inactivating mutations of PTPN2 lead to hyperactivation of the JAK-STAT pathway, conferring proliferative and survival advantages to leukemia cells, even under limited cytokine conditions. This dysregulation enhances the malignant potential of leukemic cells within the tumor microenvironment.

In solid tumors, PTPN2 also exhibits tumor-suppressive functions. In gastric cancer, reduced PTPN2 expression promotes tumor progression by influencing the tumor microenvironment. Knockdown of PTPN2 in gastric cancer cells stimulates cancer-associated fibroblasts (CAFs) to secrete IFN-γ and IL-2, which activate JAK-STAT signaling and promote cancer cell migration. Clinically, low PTPN2 expression combined with high CAF marker FSP-1 correlates with shorter survival in patients, underscoring its complex role in shaping tumor–stroma interactions.

PTPN2 also regulates anti-tumor immunity. Its loss in tumor cells enhances IFN-γ signaling, increases MHC class I expression, and improves CD8⁺ T-cell recognition and killing of tumor cells. At the same time, PTPN2 deficiency sensitizes tumors to immune checkpoint blockade, as shown in melanoma and colorectal cancer models. However, the effects are context-dependent: loss of PTPN2 in tumor cells promotes immune-mediated clearance, whereas its absence in T cells enhances their cytotoxic activity. This duality suggests that selective targeting of PTPN2 in tumor cells may amplify immunotherapy efficacy.

Clinical Implications as a Therapeutic Target

Therapeutic strategies involving PTPN2 face distinct challenges, as its function generally needs to be restored rather than inhibited. Nevertheless, in specific contexts, inhibiting PTPN2 can potentiate immune checkpoint blockade. In T-ALL, PTPN2 loss renders leukemic cells hypersensitive to JAK inhibitors such as ruxolitinib, providing a rationale for precision treatment of patients harboring PTPN2 alterations.

In solid tumors, combining PTPN2 inhibition with PD-1 blockade has shown promise in preclinical models. Tumor-specific deletion of PTPN2 enhances responsiveness to anti-PD-1 therapy by increasing IFN-γ sensitivity, promoting chemokine secretion, boosting T-cell infiltration, and improving antigen presentation, while also reshaping the immune microenvironment. Several pharmaceutical efforts are underway to develop selective PTPN2 inhibitors aimed at locally modulating tumor immunity without inducing systemic autoimmunity.

In gastric cancer, targeting downstream signaling pathways may provide therapeutic opportunities. Since PTPN2 loss promotes metastasis through JAK-STAT activation, JAK inhibitors could represent a potential treatment for aggressive tumors with low PTPN2 expression and CAF activation. Importantly, PTPN2 may exert opposing effects depending on the cell type: acting as a suppressor in cancer cells but supporting tumor progression when lost in stromal cells. This complexity emphasizes the need for cell–type–specific therapeutic strategies.

Reference

Shuai K, Liu B. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003 Nov;3(11):900-11.
Song J, Lan J, Tang J, Luo N. PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review. Int J Mol Sci. 2022 Sep 2;23(17):10025.
Zhang Y, Shuai X, Lei Y, et al. PTPN2: Advances and perspectives in cancer treatment potential and inhibitor research*. Int J Biol Macromol*. 2025 Jun;316(Pt 1):144740.

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