Rag-1 and Rag-2 genes during B lymphocyte develop-University of Cambridge School of Clinical Medicine ment (Billips et al., 1995). Cambridge CB2 2SPThe CD19-CD21 complex achieves these biological United Kingdom responses by synergistically enhancing signaling through † Departments of Medicine and Microbiology mIg. Coligating CD19 or CD21 to mIg lowers the number University of Alabama, Birmingham of mIg required for inducing increases in intracellular Birmingham Veterans Affairs Medical Center Ca 2ϩ concentration ([Ca 2ϩ ] i ) (Carter et al., 1991; Dempsey Birmingham, Alabama 35294 et al., 1996) and the proliferation of B lymphocytes (Car- ‡ National Institute for Medical Research ter and Fearon, 1992). The costimulatory effect of CD19 The Ridgeway on [Ca 2ϩ ]i is associated with the enhanced generation London NW7 1AA of inositol 1,4,5-trisphosphate [I(1,4,5)P 3 ]; ligating CD19 United Kingdom alone also generates I(1,4,5)P 3 , although the amounts are less. The mechanism for this function of CD19 is not known, but both the synergistic and the direct effects Summary of CD19 on the production of I(1,4,5)P 3 occur without its altering the tyrosine phosphorylation of phospholi-CD19 is a coreceptor that amplifies signaling by mempase C (PLC)-␥ (Carter et al., 1991), suggesting that brane immunoglobulin (mIg) to promote responses of CD19 either enhances the efficiency of PLC␥ or inthe B lymphocyte to T-dependent antigens. Vav is a creases the availability of the substrate, phosphatidylguanine nucleotide exchange factor for the Rho, Rac, inositol 4,5-bisphosphate [PI(4,5)P 2], which may become Cdc42 family of small GTPases. We found that coligatrate limiting for inositol lipid hydrolysis (Stephens et al., ing mIg and CD19 causes a synergistic increase in 1993), or does both. the tyrosine phosphorylation of CD19. PhosphorylatedCD19 also costimulates with mIg the mitogen-actityrosine-391 of CD19 binds Vav to mediate a sustained vated protein (MAP) kinases ERK2 (extracellular signalincrease in intracellular Ca 2؉ concentration. This reregulated protein kinase 2), JNK/SAPK (c-Jun N-terminal sponse correlates with activation by the CD19-Vav kinase/stress-activated protein kinase), and p38 (Li et complex of phosphatidylinositol 4-phosphate 5-kinase al., 1997;Tooze et al., 1997). Although ligating mIg or for the synthesis of phosphatidylinositol 4,5-bisphos-CD19 alone causes modest or no activation of these phate. Interaction of CD19 with Vav also mediates the kinases, their coligation causes robust activation of all synergistic activation of the mitogen-activated protein three, even at low levels of mIg cross-linking. Therefore, kinase JNK. Therefore, CD19 is a membrane adaptor at least two general pathways of signaling by mIg are protein that recruits Vav for the activation of lipid and up-regulated by CD19: phosphatidylinositol metaboprotein kinases.lism, leading to elevated [Ca 2ϩ ] i , and the MAP kinase cascades.Vav and the Rho family of small guanosine triphospha-

No abstract