T-Cell Protein Tyrosine Phosphatase, Distinctively Expressed in Activated-B-Cell-Like Diffuse Large B-Cell Lymphomas, Is the Nuclear Phosphatase of STAT6

Abstract

Diffuse large B-cell lymphomas (DLBCLs) consist of clinically distinct subtypes: germinal center B-cell (GCB)-like and activated-B-cell (ABC)-like tumors, characterized by long and short survival, respectively. We reported distinct interleukin 4 (IL-4) responsiveness and STAT6 signaling in these DLBCL subtypes. Increased nuclear dephosphorylation of phospho-STAT6 (pSTAT6) was observed in ABC-like tumors, which exhibited a different expression profile of protein tyrosine phosphatases (PTPs). Among the differentially expressed PTPs, only T-cell PTP (TCPTP) localizes to the nucleus. Herein, we report that the elevated expression of TCPTP in ABC-versus GCB-like DLBCL tumors is not due to the distinct ontogeny of these neoplasms but rather may be an acquired feature of the tumors. Moreover, we report that STAT6 may serve as a physiological nuclear substrate for TCPTP. We demonstrate interactions between endogenous TCPTP and STAT6 and delineate the domains responsible for the interaction. Overexpression of TCPTP ameliorates IL-4-induced STAT6 phosphorylation and associated gene transcription, whereas knockdown of endogenous TCPTP results in increased IL-4-induced STAT6 signaling. Moreover, we report that TCPTP protein levels may be increased in response to IL-4 and that TCPTP may serve in a negative feedback loop for the suppression of IL-4-induced signaling. Taken together, these results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors.Tyrosine phosphorylation is fundamental to the control of numerous important physiological processes, and its dysregulation can contribute to the pathogenesis of varied inherited and acquired human diseases, from immune deficiencies to cancer. Protein tyrosine phosphatases (PTPs) are a large family of enzymes that catalyze the dephosphorylation of tyrosylphosphorylated proteins, and their actions are integral to the maintenance of homeostasis and health (2, 3). T-cell PTP (TCPTP), also known as protein tyrosine phosphatase nonreceptor type 2 (PTPN2), is a classical tyrosine-specific PTP expressed predominantly in cells of hematopoietic origin. TCPTP mRNA can be alternatively spliced to generate 48-kDa and 45-kDa TCPTP variant proteins with distinct subcellular localizations: 48-kDa TCPTP is targeted to the endoplasmic reticulum by a hydrophobic C terminus (8, 16), whereas 45-kDa TCPTP (TCPTP-45) lacks the hydrophobic C terminus and is targeted to the nucleus by a bipartite nuclear localization sequence (39). Despite TCPTP-45 having an apparently exclusively nuclear localization in resting cells, specific stimuli can induce TCPTP-45 shuttling to the cytoplasm (20) where it can access cytoplasmic substrates that include the epidermal growth factor receptor (18), the insulin receptor (12), Src family protein tyrosine kinases (41), the adaptor protein p52 Shc (38), and Janus family protein tyrosine kinases 1 and 3 (JAK1 an...

Protein Tyrosine Phosphatases and Type 1 Diabetes: Genetic and Functional Implications of PTPN2 and PTPN22

“…The Janus kinases JAK1 and JAK3 are dephosphorylated by PTPN2, resulting in modulation of IL-2, IFNγ, and IFNα signaling [54], while the transcription factors STAT1, STAT3, and STAT6 are targets of PTPN2 in response to IFNγ, IL-6, and IL-4, respectively [55][56][57]. TNF has been shown to stimulate PTPN2 interaction with the adaptor protein TNF receptor-associated factor 2 (TRAF2), with subsequent dephosphorylation of c-SRC and regulation of ERK activation [58].…”

Histone H3k9 and H3k27 Acetylation Regulates IL‐4/STAT6‐Mediated Igε Transcription in B Lymphocytes

“…Previous work has shown that B cells from mice lacking STAT6 failed to produce significant amounts of IgE and IgG1 after infection with the nematode parasites (Raia et al, 2011;Turqueti-Neves et al, 2014). The binding sites of STAT6 have been found in the target regions of a variety of IL-4-mediated genes, including CD23 (Cooper et al, 2012), IL-4R (Jenkins et al, 2013), eotaxin-1 (Waddell et al, 2013), eotaxin-3 (Nakayama et al, 2010), FIZZ1 (Dasgupta et al, 2011), and in Ig germline e (Lu et al, 2007) promoters. Recently, IL-4-driven STAT6 constitutive activation has been found in various diseases, such as allergy (Hong et al, 2014), tumors (Cheah et al, 2014;Creytens et al, in press;Koelsche et al, 2014), and lymphoproliferative disorders (Rawal et al, 2013).…”

Mutation analysis of the tyrosine phosphatase PTPN2 in Hodgkin's lymphoma and T-cell non-Hodgkin's lymphoma

“…16,17 Since PTPN2 represents a phosphatase for both JAKs and STATs, and since PTPN2 was found to be mutated in HL cell line, we investigated whether mutation of PTPN2 could be responsible for the deregulation of the JAK/STAT signaling cascade in HL. 8,18 We selected a cohort of HL samples (10 nodular lymphocyte-predominant HL, 27 nodular sclerosis cHL, 6 mixedcellularity cHL, 5 lymphocyte-rich cHL, and 2 lymphocyte-depleted cHL) for a comprehensive sequence analysis of the coding region of PTPN2 using the 454 amplicon deep sequencing technology (Roche 454 GS-FLX). This technology was chosen because HL samples usually carry only a very low percentage of clonal Hodgkin's and Reed Sternberg cells; typically less than 1%.…”