Gene expression profiling studies sub-classified diffuse large B-cell lymphomas (DLBCL) into two clinically distinct types: Germinal Center B cell (GCB)-like and Activated B-cell (ABC)-like tumors, characterized by long and short survival, respectively. We have recently reported distinct responsiveness of GCB-like and ABC-like DLBCL cell lines to IL-4 stimulation. In GCB-like lymphoma cells, IL-4 leads to nuclear accumulation of phosphorylated signal transducer and activator of transcription 6 (STAT6) and induction of IL-4 target genes, while in ABC-like tumor cells there is an increased nuclear dephosphorylation of pSTAT6 and no induction of IL-4 target genes (

Lu et al:
Blood
2005
;
105
:
2924
). Furthermore, GCB-like and ABC-like DLBCL tumors exhibit a different expression profile of protein tyrosine phosphatases (PTPs). Among the distinctively expressed PTPs, only 45kDa isoform of protein tyrosine phosphatase non-receptor type 2 (PTPN2, also known as T-cell PTP-TCPTP) localizes to the nucleus. Despite PTPN2–45 having an apparent exclusively nuclear localization in resting cells, specific stimuli can induce PTPN2–45 shuttling to the cytoplasm, thus gaining access to the cytoplasmic substrates, such as the epidermal growth factor (EGF) receptor, the insulin receptor, Src family kinases, adaptor protein p52 Shc and Janus protein tyrosine kinases (JAK 1 and 3), thereby regulating multiple intracellular signaling pathways. In contrast, STAT1, 5A and 5B are the only to date known PTPN2-45 nuclear substrates. Substrate identification is a crucial step in delineating the functional spectrum of PTPN2 in vivo. Herein, we demonstrate that STAT6 may serve as a physiological nuclear substrate of PTPN2-45. Over-expression of PTPN2 leads to nuclear STAT6 dephosphorylation. By using a nuclear restricted version of PTPN2 (pEGFP-PTPN2), we show that the dephosphorylation of STAT6 is independent of PTPN2 induced JAK dephosphorylation. We demonstrate interactions between endogenous PTPN2 and STAT6 and delineate the STAT6 and PTPN2 protein domains responsible for the interaction: the catalytic domain of PTPN2 and the C terminal transactivation domain of STAT6. Furthermore, we demonstrate that over-expression of PTPN2 ameliorates IL-4 induced expression of its target genes in GCB-like DLBCL tumor cells. We observe tight control of PTPN2 at different differentiation levels of B cell lymphocytes thus suggesting that distinct expression of PTPN2 in GCB-like and ABC-like DLBCL tumors stems from different cellular origin of these lymphomas. Our findings identify STAT6 as a new nuclear target of PTPN2 and suggest that distinct PTPs expression profiles may contribute to different biological characteristics of GCB-like and ABC-like DLBCL.

Topics:
diffuse large b-cell lymphoma, phosphoric monoester hydrolases, interleukin-4, protein tyrosine phosphatase, neoplasms, lymphoma, tumor cells, adaptor signaling protein, epidermal growth factor, gene expression profiling

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2005, The American Society of Hematology
2005
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