Human SLP-65 isoforms contribute differently to activation and apoptosis of B lymphocytes.
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.
Grabbe
Annika
A
Georg August University of Göttingen, Institute of Cellular and Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germany.
Wienands
Jürgen
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D002645:Chickens / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D038041:Lymphopoiesis / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; D020033:Protein Isoforms; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4