TC-PTP-mediated regulation of p38 MAPK signaling induces epidermal apoptosis in response to UVB irradiation

T-cell protein tyrosine phosphatase (TC-PTP) is a non-receptor PTP that has been shown to have various roles in signaling pathways. Our previous studies have demonstrated that the TC-PTP deficiency in the epidermis can exacerbate hyperplastic response by inducing epidermal cell proliferation in response to tumor promoter TPA or UVB exposure. This implies that TC-PTP plays a tumor-suppressive role in the epidermis and provides protection against UVB radiation, which is well known to contribute to skin cancer development. In the present study, we aim to elucidate the molecular mechanisms by which TC-PTP influences the p38 MAPK pathway and its subsequent effects on cellular responses to UVB exposure. We utilized transgenic mice that specifically overexpress TC-PTP in the epidermis ( K5HA.Ptpn2 ) and immortalized primary keratinocytes (IPKs) derived from both FVB mice (TC-PTP/WT) and K5HA.Ptpn2 mice (TC-PTP/OVER). Upon UVB irradiation, the overexpression of TC-PTP in keratinocytes leads to an increase in apoptosis, which plays a protective role by removing damaged cells. Consistent with in vitro results, epidermal thickness induced by UVB was significantly decreased in K5HA.Ptpn2 mice. The phosphorylation of p38 MAPK was increased progressively over time, reaching its peak expression at 12 hours post-UVB exposure in both TC-PTP/OVER IPKs and K5HA.Ptpn2 mice. This effect was not observed in similarly treated control IPKs and FVB mice. Western blot analysis revealed a significant increase in the levels of cleaved Caspase-3 and PARP in TC-PTP/OVER IPKs following UVB treatment. FACS analysis confirmed that higher levels of apoptotic cells were observed in TC-PTP/OVER IPKs compared to TC-PTP/WT IPKs following UVB treatment. Similarly, annexin V staining was particularly more pronounced in TC-PTP overexpressing keratinocytes compared to control keratinocytes. Pretreatment with SB203580, p38 MAPK inhibitor, before UVB exposure led to an increase in cell viability in TC-PTP/OVER IPKs with decreased apoptotic response, suggesting that UVB-induced apoptotic response is mediated via the TC-PTP/p38 MAPK axis. Our findings reveal insights into the protective role of TC-PTP against UVB-induced skin damage via the regulation of p38 MAPK signaling pathway. Understanding the interaction between TC-PTP and the p38 MAPK signaling pathway is essential, as these underlying molecular mechanisms could be a potential therapeutic target for skin cancer prevention and treatment.