T-cell protein tyrosine phosphatase, distinctively expressed in activated-B-cell-like diffuse large B-cell lymphomas, is the nuclear phosphatase of STAT6
T-cell protein tyrosine phosphatase, distinctively expressed in activated-B-cell-like diffuse large B-cell lymphomas, is the nuclear phosphatase of STAT6
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DOI：
10.1128/mcb.01234-06
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发表时间：
2007-03-01
影响因子：
5.3
通讯作者：
Lossos, Izidore S.
中科院分区：
文献类型：
--
作者：
Lu, Xiaoqing;Chen, Jun;Lossos, Izidore S.
弥漫性大b细胞淋巴瘤（DLBCLs）由临床不同的亚型组成：生发中心b细胞（GCB）样和活化b细胞（ABC）样肿瘤，其生存期分别较长和较短。我们报道了这些DLBCL亚型中不同的白细胞介素4 （IL-4）反应性和STAT6信号传导。在abc样肿瘤中观察到磷酸化- stat6 （pSTAT6）的核去磷酸化增加，显示出蛋白酪氨酸磷酸酶（PTPs）的不同表达谱。在差异表达的PTP中，只有t细胞PTP （TCPTP）定位于细胞核。在本文中，我们报道了TCPTP在abc -与gcb样DLBCL肿瘤中的升高表达并不是由于这些肿瘤的不同个体发生，而可能是肿瘤的获得性特征。此外，我们报道STAT6可能作为TCPTP的生理核底物。我们展示了内源性TCPTP和STAT6之间的相互作用，并描述了负责相互作用的域。过表达TCPTP可改善il -4诱导的STAT6磷酸化和相关基因转录，而内源性TCPTP敲低可增加il -4诱导的STAT6信号转导。此外，我们报道TCPTP蛋白水平可能在IL-4的作用下升高，TCPTP可能在一个负反馈回路中抑制IL-4诱导的信号传导。综上所述，这些结果确定TCPTP是STAT6磷酸化的生理调节剂，并表明TCPTP在abc样dlbcl中表达的特异性增加可能有助于这些肿瘤的不同生物学特性。
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.