BLNK Binds Active H-Ras to Promote B Cell Receptor-mediated Capping and ERK Activation
BLNK Binds Active H-Ras to Promote B Cell Receptor-mediated Capping and ERK Activation
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DOI：
10.1074/jbc.m809051200
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发表时间：
2009-04-10
影响因子：
4.8
通讯作者：
Kitamura, Daisuke
中科院分区：
文献类型：
--
作者：
Imamura, Yasuhiro;Oda, Akihisa;Kitamura, Daisuke
交联的B细胞受体（BCR）聚集在细胞表面，然后组装成Ras共定位的“帽”，并转导包括Ras-ERK激活的各种细胞内信号。BCR信号诱导B细胞增殖、分化或凋亡，这取决于它们的成熟阶段。衔接蛋白BLNK结合各种信号蛋白和IG α（BCR复合物的信号亚基），并在BCR信号转导中起重要作用。在BCR交联后，BLNK被证明是ERK激活所需的，但不是Ras激活所需的，这提出了BLNK如何促进ERK激活的问题。在这里，我们证明了BLNK结合活性形式的H-Ras，它们的结合是由BCR交联促进的。我们已经鉴定了BLNK内的10个氨基酸Ras结合结构域，其对于在BLNK缺陷型B细胞中恢复BCR介导的ERK活化和抗凋亡信号传导是必需的。与CD 8 α-Ig α嵌合受体融合的Ras结合结构域可诱导BLNK缺陷型B细胞中ERK磷酸化延长、Elk 1转录激活以及受体加帽。这些结果表明，BLNK募集活性H-Ras的BCR复合物，这是必不可少的持续的表面表达的帽的形式和信号导致功能性ERK激活的BCR。
Cross-linked B cell receptor (BCR) aggregates on the cell surface, then assembles into the "cap" where Ras is co-localized, and transduces various intracellular signals including Ras-ERK activation. BCR signals induce proliferation, differentiation, or apoptosis of B cells depending on their maturational stage. The adaptor protein BLNK binds various signaling proteins and Ig alpha, a signaling subunit of the BCR complex, and plays an important role in the BCR signal transduction. BLNK was shown to be required for activation of ERK, but not of Ras, after BCR cross-linking, raising a question how BLNK facilitates ERK activation. Here we demonstrate that BLNK binds the active form of H-Ras, and their binding is facilitated by BCR cross-linking. We have identified a 10-amino acid Ras-binding domain within BLNK that is necessary for restoration of BCR-mediated ERK activation in BLNK-deficient B cells and for anti-apoptotic signaling. The Ras-binding domain fused with a CD8 alpha-Ig alpha chimeric receptor could induce prolonged ERK phosphorylation, transcriptional activation of Elk1, as well as the capping of the receptor in BLNK-deficient B cells. These results indicate that BLNK recruits active H-Ras to the BCR complex, which is essential for sustained surface expression of BCR in the form of the cap and for the signal leading to functional ERK activation.