Alternative titles; symbols
HGNC Approved Gene Symbol: PTPN2
Cytogenetic location: 18p11.21 Genomic coordinates (GRCh38): 18:12,785,478-12,884,237 (from NCBI)
The phosphorylation of proteins at tyrosine is an important regulatory component in signal transduction, neoplastic transformation, and the control of the mitotic cycle. As in systems regulated by serine or threonine phosphorylation, the phosphorylation of proteins at tyrosine is reversible. The reaction is catalyzed by protein-tyrosine phosphatases (PTPases; protein-tyrosine phosphate phosphohydrolase; EC 3.1.3.48). These enzymes appear to be highly specific for phosphotyrosyl proteins and bear little resemblance to either the protein-serine phosphatases or protein-threonine phosphatases or the acid and alkaline phosphatases. Cool et al. (1989) cloned PTPN2, which they called PTPT. The deduced protein shares 72% amino acid identity with PTP1B (PTPN1; 176885) in a 236-amino acid core region present in all PTPases.
Todd et al. (2007) noted that PTPN2 contains 10 exons.
Sakaguchi et al. (1991, 1992) used a human PTPT cDNA to assign the gene to human chromosome 18 and mouse chromosome 18 by Southern analysis of human/mouse and mouse/Chinese hamster somatic cell hybrids, respectively.
Johnson et al. (1993) mapped the PTPN2 gene to 18p11.3-p11.2 by fluorescence in situ hybridization. They identified pseudogenes on 1q22-q24 and 13q12-q13.
Kleppe et al. (2010) described the identification of focal deletions of PTPN2 in human T-cell acute lymphoblastic leukemia (T-ALL). Deletion of PTPN2 was specifically found in T-ALLs with aberrant expression of the TLX1 transcription factor oncogene (186770), including 4 cases also expressing the NUP214-ABL1 tyrosine kinase (114350). Knockdown of PTPN2 increased the proliferation and cytokine sensitivity of T-ALL cells. In addition, PTPN2 was identified as a negative regulator of NUP214-ABL1 kinase activity. Kleppe et al. (2010) concluded that their study provided genetic and functional evidence for a tumor suppressor role of PTPN2 and suggested that expression of PTPN2 may modulate response to treatment.
Colli et al. (2010) evaluated whether modulation of MDA5 (IFIH1; 606951) and PTPN2, 2 candidate genes for type 1 diabetes (222100), affects beta-cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. INS-1E cells and primary fluorescence-activated cell sorting-purified rat beta-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA polyinosinic-polycytidylic acid (PIC). PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary beta-cells and this was augmented by PTPN2 knockdown, although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. Colli et al. (2010) concluded that changes in MDA5 and PTPN2 expression modify beta-cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defense mechanism against proapoptotic signals generated by dsRNA.
Ren et al. (2015) had previously shown that mouse Sipar (FAM220A; 616628) enhanced dephosphorylation of the transcription factor Stat3 (102582) and negatively regulated its activity. Ren et al. (2015) found that Sipar interacted directly with Stat3 and Tc45 and enhanced interaction of phosphorylated Stat3 with Tc45 in nuclei of transfected MCF7 cells. Cotransfection of Tc45-competent and Tc45-depleted mouse embryonic fibroblasts revealed that Sipar inhibited Il6 (147620)-dependent Stat3 transcriptional activity mainly through Tc45.
For discussion of an association between variation in the PTPN2 gene and inflammatory bowel disease, see IBD21 (612354).
You-Ten et al. (1997) found that Ptpn2 -/- mice were born at the expected mendelian ratio and appeared healthy with no physical abnormalities at birth. However, by 2 weeks of age Ptpn2 -/- mice showed slight growth retardation, and between 3 to 5 weeks of age, they developed hunched posture, progressive closure of eyelids, decreased mobility, and diarrhea, and none survived beyond 5 weeks of age. Ptpn2 -/- mice had splenomegaly and lymphadenopathy with severe anemia and exhibited defects in bone marrow microenvironment, B-cell lymphopoiesis, and erythropoiesis, as well as impaired T- and B-cell development and function.
Colli, M. L., Moore, F., Gurzov, E. N., Ortis, F., Eizirik, D. L. MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic beta-cell responses to the viral by-product double-stranded RNA. Hum. Molec. Genet. 19: 135-146, 2010. [PubMed: 19825843] [Full Text: https://doi.org/10.1093/hmg/ddp474]
Cool, D. E., Tonks, N. K., Charbonneau, H., Walsh, K. A., Fischer, E. H., Krebs, E. G. cDNA isolated from a human T-cell library encodes a member of the protein-tyrosine-phosphatase family. Proc. Nat. Acad. Sci. 86: 5257-5261, 1989. [PubMed: 2546150] [Full Text: https://doi.org/10.1073/pnas.86.14.5257]
Johnson, C. V., Cool, D. E., Glaccum, M. B., Green, N., Fischer, E. H., Bruskin, A., Hill, D. E., Lawrence, J. B. Isolation and mapping of human T-cell protein tyrosine phosphatase sequences: localization of genes and pseudogenes discriminated using fluorescence hybridization with genomic versus cDNA probes. Genomics 16: 619-629, 1993. [PubMed: 8325634] [Full Text: https://doi.org/10.1006/geno.1993.1239]
Kleppe, M., Lahortiga, I., El Chaar, T., De Keersmaecker, K., Mentens, N., Graux, C., Van Roosbroeck, K., Ferrando, A. A., Langerak, A. W., Meijerink, J. P. P., Sigaux, F., Haferlach, T., Wlodarska, I., Vandenberghe, P., Soulier, J., Cools, J. Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nature Genet. 42: 530-535, 2010. [PubMed: 20473312] [Full Text: https://doi.org/10.1038/ng.587]
Ren, F., Geng, Y., Minami, T., Qiu, Y., Feng, Y., Liu, C., Zhao, J., Wang, Y., Fan, X., Wang, Y., Li, M., Li, J., Chang, Z. Nuclear termination of STAT3 signaling through SIPAR (STAT3-interacting protein as a repressor)-dependent recruitment of T cell tyrosine phosphatase TC-PTP. FEBS Lett. 589: 1890-1896, 2015. [PubMed: 26026268] [Full Text: https://doi.org/10.1016/j.febslet.2015.05.031]
Sakaguchi, A. Y., Sylvia, V. L., Martinez, L., Lalley, P. A., Shows, T. B., Han, E. S., Smith, E. A., Ghosh Choudhury, G. Assignment of tyrosine-specific T-cell phosphatase to conserved syntenic groups on human chromosome 18 and mouse chromosome 18. (Abstract) Cytogenet. Cell Genet. 58: 2014-2015, 1991.
Sakaguchi, A. Y., Sylvia, V. L., Martinez, L., Smith, E. A., Han, E. S., Lalley, P. A., Shows, T. B., Ghosh Choudhury, G. Assignment of tyrosine-specific T-cell phosphatase to conserved syntenic groups on human chromosome 18 and mouse chromosome 18. Genomics 12: 151-154, 1992. [PubMed: 1733852] [Full Text: https://doi.org/10.1016/0888-7543(92)90418-r]
Todd, J. A., Walker, N. M., Cooper, J. D., Smyth, D. J., Downes, K., Plagnol, V., Bailey, R., Nejentsev, S., Field, S. F., Payne, F., Lowe, C. E., Szeszko, J. S., and 30 others. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39: 857-864, 2007. [PubMed: 17554260] [Full Text: https://doi.org/10.1038/ng2068]
You-Ten, K. E., Muise, E. S., Itie, A., Michaliszyn, E., Wagner, J., Jothy, S., Lapp, W. S., Tremblay, M. L. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J. Exp. Med. 186: 683-693, 1997. [PubMed: 9271584] [Full Text: https://doi.org/10.1084/jem.186.5.683]