Herrin Brantley R, Groeger Alison L, Justement Louis B
Division of Developmental and Clinical Immunology, Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
J Biol Chem. 2005 Feb 4;280(5):3507-15. doi: 10.1074/jbc.M407690200. Epub 2004 Nov 29.
Signals transduced by the B cell antigen receptor (BCR) play a central role in regulating the functional response of the cell to antigen. Depending on the nature of the antigenic signal and the developmental or differentiation state of the B cell, antigen receptor signaling can promote either apoptosis or survival and activation. Understanding the molecular mechanisms underlying BCR-mediated apoptosis constitutes an important area of research because aberrations in programmed cell death can result in the development of autoimmunity or cancer. Expression of the adaptor protein hematopoietic Src homology 2 (HSH2) was found to significantly decrease BCR-mediated apoptosis in the murine WEHI-231 cell line. Analysis of signal transduction pathways activated in response to BCR ligation revealed that HSH2 does not significantly alter total protein tyrosine phosphorylation or Ca2+ mobilization. HSH2 does not potentiate the activation-dependent phosphorylation of AKT either. With respect to MAPK activation, HSH2 was not observed to alter the activation of ERK or p38 in response to BCR ligation, but it does significantly potentiate JNK activation. Analysis of processes directly associated with apoptosis revealed that HSH2 inhibits mitochondrial depolarization to a significant degree, whereas it has only a slight effect on caspase activation and poly ADP-ribose polymerase cleavage. BCR-induced apoptosis of WEHI-231 cells is associated with the loss of endogenous HSH2 expression within 12 h, whereas inhibition of apoptosis in response to CD40-mediated signaling leads to stabilization of HSH2 expression. Thus, endogenous HSH2 expression correlates directly with survival of WEHI-231 cells, which supports the hypothesis that HSH2 modulates the apoptotic response through its ability to directly or indirectly promote mitochondrial stability.
B细胞抗原受体（BCR）转导的信号在调节细胞对抗原的功能反应中起核心作用。根据抗原信号的性质以及B细胞的发育或分化状态，抗原受体信号传导可促进细胞凋亡或存活及激活。了解BCR介导的细胞凋亡的分子机制是一个重要的研究领域，因为程序性细胞死亡的异常可能导致自身免疫或癌症的发生。研究发现，衔接蛋白造血Src同源2（HSH2）的表达可显著降低小鼠WEHI-231细胞系中BCR介导的细胞凋亡。对BCR连接后激活的信号转导通路的分析表明，HSH2不会显著改变总蛋白酪氨酸磷酸化或Ca2+动员。HSH2也不会增强AKT的激活依赖性磷酸化。关于丝裂原活化蛋白激酶（MAPK）的激活，未观察到HSH2改变BCR连接后ERK或p38的激活，但它确实显著增强了JNK的激活。对与细胞凋亡直接相关的过程的分析表明，HSH2在很大程度上抑制线粒体去极化，而对半胱天冬酶激活和聚ADP核糖聚合酶裂解只有轻微影响。BCR诱导的WEHI-231细胞凋亡与12小时内内源性HSH2表达的丧失有关，而对CD40介导的信号传导的细胞凋亡抑制导致HSH2表达的稳定。因此，内源性HSH2表达与WEHI-231细胞的存活直接相关，这支持了HSH2通过其直接或间接促进线粒体稳定性的能力来调节细胞凋亡反应的假设。
