Overexpression of TC-PTP in murine epidermis attenuates skin tumor formation


T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, has been shown to function as a tumor suppressor during skin carcinogenesis. In the current study, we generated a novel epidermal-specific TC-PTP-overexpressing (K5HA.Ptpn2) mouse model to show that TC-PTP contributes to the attenuation of chemically induced skin carcinogenesis through the synergistic regulation of STAT1, STAT3, STAT5, and PI3K/AKT signaling. We found overexpression of TC-PTP increased epidermal sensitivity to DMBA-induced apoptosis and it decreased TPA-mediated hyperproliferation, coinciding with reduced epidermal thickness. Inhibition of STAT1, STAT3, STAT5, or AKT reversed the effects of TC-PTP overexpression on epidermal survival and proliferation. Mice overexpressing TC-PTP in the epidermis developed significantly reduced numbers of tumors during skin carcinogenesis and presented a prolonged latency of tumor initiation. Examination of human papillomas and squamous cell carcinomas (SCCs) revealed that TC-PTP expression was significantly reduced and TC-PTP expression was inversely correlated with the increased grade of SCCs. Our findings demonstrate that TC-PTP is a potential therapeutic target for the prevention of human skin cancer given that it is a major negative regulator of oncogenic signaling.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Generation of epidermal-specific K5HA.Ptpn2 transgenic mouse.
Fig. 2: Effect of TC-PTP overexpression on DMBA-induced apoptosis in epidermis.
Fig. 3: TC-PTP overexpression sensitizes DMBA-induced apoptosis through regulation of STAT and AKT signaling pathways.
Fig. 4: Inhibition of STAT1, STAT3, STAT5, or AKT on DMBA-induced apoptosis in keratinocytes.
Fig. 5: Effect of TC-PTP overexpression on epidermal hyperproliferation induced by TPA.
Fig. 6: Overexpression of TC-PTP in epidermis reduces TPA-induced cell proliferation and survival through the regulation of STAT1, STAT3, STAT5, and PI3K/AKT signaling.
Fig. 7: Inhibition of STAT1, STAT3, STAT5, PI3K, or AKT during TPA-induced keratinocyte survival and proliferation.
Fig. 8: TC-PTP overexpression reduces tumor formation in the epidermis during two-stage skin carcinogenesis.
Fig. 9: TC-PTP expression in human skin tumors.


  1. 1.

    Lim WA, Pawson T. Phosphotyrosine signaling: evolving a new cellular communication system. Cell. 2010;142:661–7.

  2. 2.

    Hunter T. Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol. 2009;21:140–6.

  3. 3.

    Casaletto JB, McClatchey AI. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer. 2012;12:387–400.

  4. 4.

    Hendriks WJ, Elson A, Harroch S, Stoker AW. Protein tyrosine phosphatases: functional inferences from mouse models and human diseases. FEBS J. 2008;275:816–30.

  5. 5.

    Hendriks WJ, Pulido R. Protein tyrosine phosphatase variants in human hereditary disorders and disease susceptibilities. Biochim Biophys Acta. 2013;1832:1673–96.

  6. 6.

    Cuppen E, Wijers M, Schepens J, Fransen J, Wieringa B, Hendriks W. A FERM domain governs apical confinement of PTP-BL in epithelial cells. J Cell Sci. 1999;112:3299–308.

  7. 7.

    Cool DE, Tonks NK, Charbonneau H, Walsh KA, Fischer EH, Krebs EG. cDNA isolated from a human T-cell library encodes a member of the protein-tyrosine-phosphatase family. Proc Natl Acad Sci USA. 1989;86:5257–61.

  8. 8.

    Mosinger B Jr., Tillmann U, Westphal H, Tremblay ML. Cloning and characterization of a mouse cDNA encoding a cytoplasmic protein-tyrosine-phosphatase. Proc Natl Acad Sci USA. 1992;89:499–503.

  9. 9.

    Bourdeau A, Dube N, Tremblay ML. Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP. Curr Opin Cell Biol. 2005;17:203–9.

  10. 10.

    Tillmann U, Wagner J, Boerboom D, Westphal H, Tremblay ML. Nuclear localization and cell cycle regulation of a murine protein tyrosine phosphatase. Mol Cell Biol. 1994;14:3030–40.

  11. 11.

    Kamatkar S, Radha V, Nambirajan S, Reddy RS, Swarup G. Two splice variants of a tyrosine phosphatase differ in substrate specificity, DNA binding, and subcellular location. J Biol Chem. 1996;271:26755–61.

  12. 12.

    Kim M, Morales LD, Baek M, Slaga TJ, DiGiovanni J, Kim DJ. UVB-induced nuclear translocation of TC-PTP by AKT/14-3-3sigma axis inhibits keratinocyte survival and proliferation. Oncotarget. 2017;8:90674–92.

  13. 13.

    Dube N, Tremblay ML. Involvement of the small protein tyrosine phosphatases TC-PTP and PTP1B in signal transduction and diseases: from diabetes, obesity to cell cycle, and cancer. Biochim Biophys Acta. 2005;1754:108–17.

  14. 14.

    Xu D, Qu CK. Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci. 2008;13:4925–32.

  15. 15.

    Kim M, Morales LD, Jang IS, Cho YY, Kim DJ. Protein tyrosine phosphatases as potential regulators of STAT3 signaling. Int J Mol Sci. 2018;19:2708.

  16. 16.

    Shields BJ, Wiede F, Gurzov EN, Wee K, Hauser C, Zhu HJ, et al. TCPTP regulates SFK and STAT3 signaling and is lost in triple-negative breast cancers. Mol Cell Biol. 2013;33:557–70.

  17. 17.

    Kleppe M, Lahortiga I, El Chaar T, De Keersmaecker K, Mentens N, Graux C, et al. Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat Genet. 2010;42:530–5.

  18. 18.

    Lee CF, Ling ZQ, Zhao T, Fang SH, Chang WC, Lee SC, et al. Genomic-wide analysis of lymphatic metastasis-associated genes in human hepatocellular carcinoma. World J Gastroenterol. 2009;15:356–65.

  19. 19.

    Karlsson E, Veenstra C, Emin S, Dutta C, Perez-Tenorio G, Nordenskjold B, et al. Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer. Breast Cancer Res Treat. 2015;153:31–40.

  20. 20.

    Lee H, Kim M, Baek M, Morales LD, Jang IS, Slaga TJ, et al. Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development. Sci Rep. 2017;7:45077.

  21. 21.

    Baek M, Kim M, Lim JS, Morales LD, Hernandez J, Mummidi S, et al. Epidermal-specific deletion of TC-PTP promotes UVB-induced epidermal cell survival through the regulation of Flk-1/JNK signaling. Cell Death Dis. 2018;9:730.

  22. 22.

    Manguso RT, Pope HW, Zimmer MD, Brown FD, Yates KB, Miller BC, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547:413–8.

  23. 23.

    Lee H, Morales LD, Slaga TJ, Kim DJ. Activation of T-cell protein-tyrosine phosphatase suppresses keratinocyte survival and proliferation following UVB irradiation. J Biol Chem. 2015;290:13–24.

  24. 24.

    Hennings H, Glick AB, Lowry DT, Krsmanovic LS, Sly LM, Yuspa SH. FVB/N mice: an inbred strain sensitive to the chemical induction of squamous cell carcinomas in the skin. Carcinogenesis. 1993;14:2353–8.

  25. 25.

    Abel EL, Angel JM, Kiguchi K, DiGiovanni J. Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applications. Nat Protoc. 2009;4:1350–62.

  26. 26.

    DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther. 1992;54:63–128.

  27. 27.

    Kim DJ, Tremblay ML, Digiovanni J. Protein tyrosine phosphatases, TC-PTP, SHP1, and SHP2, cooperate in rapid dephosphorylation of Stat3 in keratinocytes following UVB irradiation. PLoS ONE. 2010;5:e10290.

  28. 28.

    Bozeman R, Abel EL, Macias E, Cheng T, Beltran L, DiGiovanni J. A novel mechanism of skin tumor promotion involving interferon-gamma (IFNgamma)/signal transducer and activator of transcription-1 (Stat1) signaling. Mol Carcinog. 2015;54:642–53.

  29. 29.

    Chan KS, Carbajal S, Kiguchi K, Clifford J, Sano S, DiGiovanni J. Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis. Cancer Res. 2004;64:2382–9.

  30. 30.

    Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science. 1997;278:1630–2.

  31. 31.

    Zhang JJ, Zhao Y, Chait BT, Lathem WW, Ritzi M, Knippers R, et al. Ser727-dependent recruitment of MCM5 by Stat1alpha in IFN-gamma-induced transcriptional activation. EMBO J. 1998;17:6963–71.

  32. 32.

    Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82:241–50.

  33. 33.

    Agrawal S, Agarwal ML, Chatterjee-Kishore M, Stark GR, Chisolm GM. Stat1-dependent, p53-independent expression of p21(waf1) modulates oxysterol-induced apoptosis. Mol Cell Biol. 2002;22:1981–92.

  34. 34.

    DeVries TA, Kalkofen RL, Matassa AA, Reyland ME. Protein kinase Cdelta regulates apoptosis via activation of STAT1. J Biol Chem. 2004;279:45603–12.

  35. 35.

    Zimmerman MA, Rahman NT, Yang D, Lahat G, Lazar AJ, Pollock RE, et al. Unphosphorylated STAT1 promotes sarcoma development through repressing expression of Fas and bad and conferring apoptotic resistance. Cancer Res. 2012;72:4724–32.

  36. 36.

    Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627–44.

  37. 37.

    Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46:372–83.

  38. 38.

    Dlugosz AA, Glick AB, Tennenbaum T, Weinberg WC, Yuspa SH. Isolation and utilization of epidermal keratinocytes for oncogene research. Methods Enzymol. 1995;254:3–20.

Download references


We thank H. Lee for technical assistance. This work was supported by NIH/NIEHS ES022250 (to D.J. Kim) and NIH/NIAID AI119131 (to S. Mummidi).

Author information




DJK conceived the project, designed the study, and interpreted the results. WJK, SM, CJ, AT, ISJ, and TJS also contributed to interpretation of the results. CJL, LDM, MK, SAO, and JH performed experiments. DJK wrote the paper. All authors discussed the results and commented on the paper.

Corresponding author

Correspondence to Dae Joon Kim.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kim, M., Morales, L.D., Lee, C.J. et al. Overexpression of TC-PTP in murine epidermis attenuates skin tumor formation. Oncogene 39, 4241–4256 (2020). https://doi.org/10.1038/s41388-020-1282-8

Download citation