Grabbe Annika, Wienands Jürgen
Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germany.
Blood. 2006 Dec 1;108(12):3761-8. doi: 10.1182/blood-2006-02-005397. Epub 2006 Aug 15.
The SH2 domain-containing leukocyte adaptor protein of 65 kDa (SLP-65) is the key effector for signaling downstream of the B-cell antigen receptor (BCR). SLP-65 controls not only B lymphopoiesis and humoral immunity but also possesses a yet poorly defined tumor suppressor activity that is lost in many cases of acute lymphoblastic leukemia. We found that the 2 isoforms of human SLP-65 are differentially involved in positive and negative B-cell signaling. Reconstitution experiments revealed that an atypical SH3 domain-binding motif, which is present in the long but not in the short SLP-65 isoform, mediates association to Grb2 and suppresses activation of mitogen-activated protein kinases p38 and JNK as well as up-regulation of c-Fos expression. In turn, the short isoform activates not only AP1-driven but also NF-kappaB-driven gene transcription more potently than the long isoform. Conversely, the long rather than the short SLP-65 isoform promotes BCR-induced B-cell apoptosis. Our data further delineate the structural requirements of positive and negative SLP-65 signal transduction in normal and neoplastic cells.
含SH2结构域的65 kDa白细胞衔接蛋白（SLP-65）是B细胞抗原受体（BCR）下游信号传导的关键效应分子。SLP-65不仅控制B淋巴细胞生成和体液免疫，还具有尚未明确界定的肿瘤抑制活性，这种活性在许多急性淋巴细胞白血病病例中丧失。我们发现人类SLP-65的两种异构体分别参与B细胞的正向和负向信号传导。重组实验表明，一种非典型的SH3结构域结合基序存在于长型而非短型SLP-65异构体中，它介导与Grb2的结合，并抑制丝裂原活化蛋白激酶p38和JNK的激活以及c-Fos表达的上调。反过来，短型异构体比长型异构体更有效地激活不仅由AP1驱动而且由NF-κB驱动的基因转录。相反，长型而非短型SLP-65异构体促进BCR诱导的B细胞凋亡。我们的数据进一步阐明了正常细胞和肿瘤细胞中SLP-65正向和负向信号转导的结构要求。
