Biomedical subjects

T Kurosaki

Publications and source records attributed to T Kurosaki.

At least 19 recordsLinked to original sources

PubMed2001

Regulation of Ca2+-release-activated Ca2+ current (Icrac) by ryanodine receptors in inositol 1,4,5-trisphosphate-receptor-deficient DT40 cells.

Persistence of capacitative Ca(2+) influx in inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R)-deficient DT40 cells (DT40(IP(3)R-/-)) raises the question of whether gating of Ca(2+)-release activated Ca(2+) current (I(crac)) by conformational coupling to Ca(2+)-release channels is a general mechanism of gating of these channels. In the present work we examined the properties and mechanism of activation of I(crac) Ca(2+) current in wild-type and DT40(IP(3)R-/-) cells. In both cell types passive depletion of internal Ca(2+) stores by infusion of EGTA activated a Ca(2+) current with similar characteristics and time course. The current was highly Ca(2+)-selective and showed strong inward rectification, all typical of I(crac). The activator of ryanodine receptor (RyR), cADP-ribose (cADPR), facilitated activation of I(crac), and the inhibitors of the RyRs, 8-N-cADPR, ryanodine and Ruthenium Red, all inhibited I(crac) activation in DT40(IP(3)R-/-) cells, even after complete depletion of intracellular Ca(2+) stores by ionomycin. Wild-type and DT40(IP(3)R-/-) cells express RyR isoforms 1 and 3. RyR levels were adapted in DT40(IP(3)R-/-) cells to a lower RyR3/RyR1 ratio than in wild-type cells. These results suggest that IP(3)Rs and RyRs can efficiently gate I(crac) in DT40 cells and explain the persistence of I(crac) gating by internal stores in the absence of IP(3)Rs.

Blotting, Western↗

PubMed2001

PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine.

PD-1 is an immunoreceptor that belongs to the immunoglobulin (Ig) superfamily and contains two tyrosine residues in the cytoplasmic region. Studies on PD-1-deficient mice have shown that PD-1 plays critical roles in establishment and/or maintenance of peripheral tolerance, but the mode of action is totally unknown. To study the molecular mechanism for negative regulation of lymphocytes through the PD-1 receptor, we generated chimeric molecules composed of the IgG Fc receptor type IIB (Fc gamma RIIB) extracellular region and the PD-1 cytoplasmic region and expressed them in a B lymphoma cell line, IIA1.6. Coligation of the cytoplasmic region of PD-1 with the B cell receptor (BCR) in IIA1.6 transformants inhibited BCR-mediated growth retardation, Ca(2+) mobilization, and tyrosine phosphorylation of effector molecules, including Ig beta, Syk, phospholipase C-gamma 2 (PLC gamma 2), and ERK1/2, whereas phosphorylation of Lyn and Dok was not affected. Mutagenesis studies indicated that these inhibitory effects do not require the N-terminal tyrosine in the immunoreceptor tyrosine-based inhibitory motif-like sequence, but do require the other tyrosine residue in the C-terminal tail. This tyrosine was phosphorylated and recruited src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2) on coligation of PD-1 with BCR. These results show that PD-1 can inhibit BCR signaling by recruiting SHP-2 to its phosphotyrosine and dephosphorylating key signal transducers of BCR signaling.

Animals↗

PubMed2001

Four tyrosine residues in phospholipase C-gamma 2, identified as Btk-dependent phosphorylation sites, are required for B cell antigen receptor-coupled calcium signaling.

Activation of phospholipase C-gamma2 (PLCgamma2) is the critical step in B cell antigen receptor (BCR)-coupled calcium signaling. Although genetic dissection experiments on B cells have demonstrated that Bruton's tyrosine kinase (Btk) and Syk are required for activating PLCgamma2, the exact activation mechanism of PLCgamma2 by these kinases has not been established. We identify the tyrosine residues 753, 759, 1197, and 1217 in rat PLCgamma2 as Btk-dependent phosphorylation sites by using an in vitro kinase assay. To evaluate the role of these tyrosine residues in phosphorylation-dependent activation of PLCgamma2, PLCgamma2-deficient DT40 cells were reconstituted with a series of mutant PLCgamma2s in which the phenylalanine was substituted for tyrosine. Substitution of all four tyrosine residues almost completely eliminated the BCR-induced PLCgamma2 phosphorylation, indicating that these residues include the major phosphorylation sites upon BCR engagement. Cells expressing PLCgamma2 with a single substitution exhibited some extent of reduction in calcium mobilization, whereas those expressing quadruple mutant PLCgamma2 showed greatly reduced calcium response. These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as Btk-dependent phosphorylation sites in vitro, coordinately contribute to BCR-induced activation of PLCgamma2.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2001

MIST functions through distinct domains in immunoreceptor signaling in the presence and absence of LAT.

MIST (also termed Clnk) is an adaptor protein structurally related to SLP-76 and BLNK/BASH/SLP-65 hematopoietic cell-specific adaptor proteins. By using the BLNK-deficient DT40 chicken B cell system, we demonstrated MIST functions through distinct intramolecular domains in immunoreceptor signaling depending on the availability of linker for activation of T cells (LAT). MIST can partially restore the B cell antigen receptor (BCR) signaling in the BLNK-deficient cells, which requires phosphorylation of the two N-terminal tyrosine residues. Co-expression of LAT with MIST fully restored the BCR signaling and dispenses with the requirement of the two tyrosines in MIST for BCR signaling. However, some other tyrosine(s), as well as the Src homology (SH) 2 domain and the two proline-rich regions in MIST, is still required for full reconstitution of the BCR signaling, in cooperation with LAT. The C-terminal proline-rich region of MIST is dispensable for the LAT-aided full restoration of MAP kinase activation, although it is responsible for the interaction with LAT and for the localization in glycolipid-enriched microdomains. On the other hand, the N-terminal proline-rich region, which is a binding site of the SH3 domain of phospholipase Cgamma, is essential for BCR signaling. These results revealed a marked plasticity of MIST function as an adaptor in the cell contexts with or without LAT.

Adaptor Proteins, Signal Transducing↗

PubMed2001

A conditional form of Bruton's tyrosine kinase is sufficient to activate multiple downstream signaling pathways via PLC Gamma 2 in B cells.

BACKGROUND: Bruton's tyrosine kinase (Btk) is essential for B cell development and function. Mutations of Btk elicit X-linked agammaglobulinemia in humans and X-linked immunodeficiency in the mouse. Btk has been proposed to participate in B cell antigen receptor-induced signaling events leading to activation of phospholipase C-gamma2 (PLCgamma2) and calcium mobilization. However it is unclear whether Btk activation is alone sufficient for these signaling events, and whether Btk can activate additional pathways that do not involve PLCgamma2. To address such issues we have generated Btk:ER, a conditionally active form of the kinase, and expressed it in the PLCgamma2-deficient DT40 B cell line. RESULTS: Activation of Btk:ER was sufficient to induce multiple B cell signaling pathways in PLCgamma2-sufficient DT40 cells. These included tyrosine phosphorylation of PLCgamma2, mobilization of intracellular calcium, activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways, and apoptosis. In DT40 B cells deficient for PLCgamma2, Btk:ER activation failed to induce the signaling events described above with the consequence that the cells failed to undergo apoptosis. CONCLUSIONS: These data suggest that Btk:ER regulates downstream signaling pathways primarily via PLCgamma2 in B cells. While it is not known whether activated Btk:ER precisely mimics activated Btk, this conditional system will likely facilitate the dissection of the role of Btk and its family members in a variety of biological processes in many different cell types.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2001

LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability.

The molecular mechanisms that regulate basal or background entry of divalent cations into mammalian cells are poorly understood. Here we describe the cloning and functional characterization of a Ca2+- and Mg2+-permeable divalent cation channel, LTRPC7 (nomenclature compatible with that proposed in ref. 1), a new member of the LTRPC family of putative ion channels. Targeted deletion of LTRPC7 in DT-40 B cells was lethal, indicating that LTRPC7 has a fundamental and nonredundant role in cellular physiology. Electrophysiological analysis of HEK-293 cells overexpressing recombinant LTRPC7 showed large currents regulated by millimolar levels of intracellular Mg.ATP and Mg.GTP with the permeation properties of a voltage-independent divalent cation influx pathway. Analysis of several cultured cell types demonstrated small magnesium-nucleotide-regulated metal ion currents (MagNuM) with regulation and permeation properties essentially identical to the large currents observed in cells expressing recombinant LTRPC7. Our data indicate that LTRPC7, by virtue of its sensitivity to physiological Mg.ATP levels, may be involved in a fundamental process that adjusts plasma membrane divalent cation fluxes according to the metabolic state of the cell.

Adenosine Triphosphate↗

PubMed2001

Ca(2+)-sensor region of IP(3) receptor controls intracellular Ca(2+) signaling.

Many important cell functions are controlled by Ca(2+) release from intracellular stores via the inositol 1,4,5-trisphosphate receptor (IP(3)R), which requires both IP(3) and Ca(2+) for its activity. Due to the Ca(2+) requirement, the IP(3)R and the cytoplasmic Ca(2+) concentration form a positive feedback loop, which has been assumed to confer regenerativity on the IP(3)-induced Ca(2+) release and to play an important role in the generation of spatiotemporal patterns of Ca(2+) signals such as Ca(2+) waves and oscillations. Here we show that glutamate 2100 of rat type 1 IP(3)R (IP(3)R1) is a key residue for the Ca(2+) requirement. Substitution of this residue by aspartate (E2100D) results in a 10-fold decrease in the Ca(2+) sensitivity without other effects on the properties of the IP(3)R1. Agonist-induced Ca(2+) responses are greatly diminished in cells expressing the E2100D mutant IP(3)R1, particularly the rate of rise of initial Ca(2+) spike is markedly reduced and the subsequent Ca(2+) oscillations are abolished. These results demonstrate that the Ca(2+) sensitivity of the IP(3)R is functionally indispensable for the determination of Ca(2+) signaling patterns.

Adenosine Triphosphate↗

PubMed2001

Assessment of the role of the inositol 1,4,5-trisphosphate receptor in the activation of transient receptor potential channels and store-operated Ca2+ entry channels.

The mechanism for coupling between Ca(2+) stores and store-operated channels (SOCs) is an important but unresolved question. Although SOCs have not been molecularly identified, transient receptor potential (TRP) channels share a number of operational parameters with SOCs. The question of whether activation of SOCs and TRP channels is mediated by the inositol 1,4,5-trisphosphate receptor (InsP(3)R) was examined using the permeant InsP(3)R antagonist, 2-aminoethoxydiphenyl borate (2-APB) in both mammalian and invertebrate systems. In HEK293 cells stably transfected with human TRPC3 channels, the actions of 2-APB to block carbachol-induced InsP(3)R-mediated store release and carbachol-induced Sr(2+) entry through TRPC3 channels were both reversed at high agonist levels, suggesting InsP(3)Rs mediate TRPC3 activation. However, electroretinogram recordings of the light-induced current in Drosophila revealed that the TRP channel-mediated responses in wild-type as well as trp and trpl mutant flies were all inhibited by 2-APB. This action of 2-APB is likely InsP(3)R-independent since InsP(3)Rs are dispensable for the light response. We used triple InsP(3)R knockout DT40 chicken B-cells to further assess the role of InsP(3)Rs in SOC activation. (45)Ca(2+) flux analysis revealed that although DT40 wild-type cells retained normal InsP(3)Rs mediating 2-APB-sensitive Ca(2+) release, the DT40InsP(3)R-k/o cells were devoid of functional InsP(3)Rs. Using intact cells, all parameters of Ca(2+) store function and SOC activation were identical in DT40wt and DT40InsP(3)R-k/o cells. Moreover, in both cell lines SOC activation was completely blocked by 2-APB, and the kinetics of action of 2-APB on SOCs (time dependence and IC(50)) were identical. The results indicate that (a) the action of 2-APB on Ca(2+) entry is not mediated by the InsP(3)R and (b) the effects of 2-APB provide evidence for an important similarity in the function of invertebrate TRP channels, mammalian TRP channels, and mammalian store-operated channels.

Adenosine↗

PubMed2001

BLNK mediates Syk-dependent Btk activation.

Btk is a critical molecule in B cell antigen receptor (BCR)-coupled signaling, and its activity is regulated by Lyn and Syk. Although the molecular mechanism of Lyn-dependent Btk activation has been investigated, that of Syk-dependent Btk activation has remained unidentified. We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity. This phosphorylation depends on the interaction of Btk and BLNK by means of the Btk-Src homology 2 domain. The existence of such an activation mechanism is supported by the observation that the BCR-induced Btk phosphorylation and activation are significantly reduced in BLNK-deficient B cells as well as in Syk-deficient B cells. Although previous observations have identified the function of BLNK as the linker that integrates the action of Btk and Syk into downstream effectors such as phospholipase Cgamma2, our present study indicates another function of BLNK that connects the activity of Syk to that of Btk.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Role of the phospholipase C-inositol 1,4,5-trisphosphate pathway in calcium release-activated calcium current and capacitative calcium entry.

We investigated the putative roles of phospholipase C, polyphosphoinositides, and inositol 1,4,5-trisphosphate (IP(3)) in capacitative calcium entry and calcium release-activated calcium current (I(crac)) in lacrimal acinar cells, rat basophilic leukemia cells, and DT40 B-lymphocytes. Inhibition of phospholipase C with blocked calcium entry and I(crac) activation whether in response to a phospholipase C-coupled agonist or to calcium store depletion with thapsigargin. Run-down of cellular polyphosphoinositides by concentrations of wortmannin that block phosphatidylinositol 4-kinase completely blocked calcium entry and I(crac). The membrane-permeant IP(3) receptor inhibitor, 2-aminoethoxydiphenyl borane, blocked both capacitative calcium entry and I(crac). However, it is likely that 2-aminoethoxydiphenyl borane does not inhibit through an action on the IP(3) receptor because the drug was equally effective in wild-type DT40 B-cells and in DT40 B-cells whose genes for all three IP(3) receptors had been disrupted. Intracellular application of another potent IP(3) receptor antagonist, heparin, failed to inhibit activation of I(crac). Finally, the inhibition of I(crac) activation by or wortmannin was not reversed or prevented by direct intracellular application of IP(3). These findings indicate a requirement for phospholipase C and for polyphosphoinositides for activation of capacitative calcium entry. However, the results call into question the previously suggested roles of IP(3) and IP(3) receptor in this mechanism, at least in these particular cell types.

Androstadienes↗

PubMed2001

Negative control of store-operated Ca2+ influx by B cell receptor cross-linking.

An increase in the intracellular Ca(2+) concentration by B cell receptor (BCR) cross-linking plays important roles in the regulation of B cell functions. [Ca(2+)](i) is regulated by Ca(2+) release from the Ca(2+) store as well as store-operated Ca(2+) influx (SOC). Protein tyrosine kinases downstream of BCR cross-linking were shown to regulate the mechanism for Ca(2+) release. However, it remains elusive whether BCR cross-linking regulates SOC or not. In this study, we examined the effect of BCR cross-linking on thapsigargin-induced SOC in the DT40 B cells. We found that the SOC-mediated increase in intracellular Ca(2+) concentration was inhibited by BCR cross-linking. Using a membrane-potential-sensitive dye, we found that BCR cross-linking induced depolarization, which is expected to decrease the driving force of Ca(2+) influx and SOC channel conductance. When membrane potential was held constant by the transmembrane K(+) concentration gradient in the presence of valinomycin, the BCR-mediated inhibition of SOC was still observed. Thus, the BCR-mediated inhibition of SOC involves both depolarization-dependent and depolarization-independent mechanisms of SOC inhibition. The depolarization-independent inhibition of the SOC was abolished in Lyn-deficient, but not in Bruton's tyrosine kinase-, Syk- or SHIP (Src homology 2 domain containing phosphatidylinositol 5'-phosphatase)-deficient cells, indicating that Lyn is involved in the inhibition. These results show novel pathways of BCR-mediated SOC regulations.

Animals↗

PubMed2001

MEKK1 is essential for DT40 cell apoptosis in response to microtubule disruption.

Vinblastine and other microtubule-damaging agents, such as nocodazole and paclitaxel, cause cell cycle arrest at the G2/M transition and promote apoptosis in eukaryotic cells. The roles of these drugs in disrupting microtubule dynamics and causing cell cycle arrest are well characterized. However, the mechanisms by which these agents promote apoptosis are poorly understood. We disrupted the MEKK1 kinase domain in chicken bursal B-cell line DT40 by homologous recombination and have shown that it is essential for both vinblastine-mediated apoptosis and vinblastine-mediated c-Jun N-terminal protein kinase activation. In addition, our data indicate that vinblastine-mediated apoptosis in DT40 cells requires new protein synthesis but does not require G2/M arrest, suggesting that vinblastine-mediated cell cycle arrest and apoptosis are two independent processes.

Animals↗

PubMed2001

Regulation of phospholipase C-gamma2 and phosphoinositide 3-kinase pathways by adaptor proteins in B lymphocytes.

The importance of phosphoinositide 3-kinase (PI3K) and phospholipase C (PLC)-gamma2 in B cell function and development has been highlighted by gene targeting experiments in mice. In fact, these knockout mice exhibit a profound inhibition of proliferative responses upon B cell receptor (BCR) engagement. The molecular connections between these effectors and upstream tyrosine kinases such as Syk have been studied intensively in the past few years. This mechanism involves the action of cytoplasmic adaptor molecules, which participate in forming multicomponent signaling complexes, thereby directing the appropriate subcellular localization of effector enzymes. In addition to these cytoplasmic adaptor proteins, cell surface coreceptors can be viewed as transmembrane adaptor proteins, because coreceptors can also change the localization of effector enzymes, which in turn modulates the BCR-initiated signals.

Animals↗

PubMed2001

Independent association of angiogenesis index with outcome in prostate cancer.

New molecular factors have been characterized that are associated with the prognosis of prostate carcinoma patients, including p53 status and angiogenesis. We reported recently that mutant p53 (mp53) was associated with decreased expression of an endogenous inhibitor of angiogenesis, thrombospondin-1 (TSP-1), and increased microvessel density in melanoma and breast cancer. In this study, we performed a similar analysis on primary prostate carcinoma to determine whether these factors were associated with each other or patient outcomes. Paraffin-embedded specimens of 98 cases of primary prostate carcinoma were obtained and examined to confirm tissue diagnosis and Gleason scores. Carcinoma-specific levels of p53, TSP-1, and tumor angiogenesis were determined using semiquantitative immunohistochemistry (IHC) methods. Acquisition of mp53 was significantly associated with decreased TSP-1 (P = 0.002) and increased angiogenesis (P < 0.0001). An angiogenesis index integrating mp53, TSP-1, and angiogenesis (CD31) scores was found to be an independent predictor of survival in univariate and multivariate analyses that included Gleason score, clinical stage, and patient age. Further validation of the angiogenesis index in prostate carcinoma may provide a new tool to stratify patient risk.

Adenocarcinoma↗

PubMed2000

Asian patients with gastric carcinoma in the United States exhibit unique clinical features and superior overall and cancer specific survival rates.

BACKGROUND: The 5-year survival rate from gastric carcinoma, stratified by stage, is markedly greater in the Far East than in the United States. This survival rate advantage may reflect differences in diagnostic criteria, more complete staging, more radical surgery, or less aggressive tumor biology. METHODS: A historic cohort of consecutive cases of gastric carcinoma reported to the population-based California Cancer Registries of Orange, San Diego and Imperial Counties from 1984 to 1996 was studied. Factors associated with Asian race were profiled using logistic regression. Multivariate survival analyses were performed using a Cox proportional hazard model. RESULTS: Two thousand four hundred sixteen patients (64%) were non-Latino white; 690 (18%) were Latino; 94 (2.5%) were black; 541 (14%) were of Asian descent: Korean (22%), Vietnamese (20%), Japanese (20%), Chinese (14%), and Filipino (12%). Asian patients were more likely to have localized (lymph node negative) disease (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.23-2.10), less likely to have tumors of the gastroesophageal junction (OR, 0.22; 95% CI, 0.15-0.31,), and less likely to be older than 50 years (OR, 0.58; 95% CI, 0.43-0.77). Asian patients with gastric carcinoma were twice as likely as non-Latino whites to be alive at 5 years (20.9% vs. 10.2%; P < 0.0001). Multivariate analyses indicated that whites had an increased risk of dying from all causes (relative risk [RR], 1.34; 95% CI, 1.16-1.55; P < 0.01) and of dying from cancer in comparison to Asian patients (RR, 1.26; 95% CI, 1.07-1.48; P < 0.05). CONCLUSIONS: Asians who received a diagnosis of gastric carcinoma in the United States have less advanced disease than non-Asians. The increased proportion of localized disease and improved survival rates of patients of Asian descent in the United States is consistent with less aggressive tumor biology.

Adult↗

PubMed2000

Functional complementation of BLNK by SLP-76 and LAT linker proteins.

Recent studies have demonstrated a requirement for the SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) and LAT (linker for activation of T cells) adaptor/linker proteins in T cell antigen receptor activation and T cell development as well as the BLNK (B cell linker) linker protein in B cell antigen receptor (BCR) signal transduction and B cell development. Whereas the SLP-76 and LAT adaptor proteins are expressed in T, natural killer, and myeloid cells and platelets, BLNK is preferentially expressed in B cells and monocytes. Although BLNK is structurally homologous to SLP-76, BLNK interacts with a variety of downstream signaling proteins that interact directly with both SLP-76 and LAT. Here, we demonstrate that neither SLP-76 nor LAT alone is sufficient to restore the signaling deficits observed in BLNK-deficient B cells. Conversely, the coexpression of SLP-76 and LAT together restored BCR-inducible calcium responses as well as activation of all three families of mitogen-activated protein kinases. Together, these data suggest functional complementation of SLP-76 and LAT in T cell antigen receptor function with BLNK in BCR function.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane.

B cell linker protein (BLNK) and Src homology 2 domain-containing leukocyte protein of 76 kD (SLP-76) are adaptor proteins required for B cell receptor (BCR) and T cell receptor function, respectively. Here, we show that expression of SLP-76 cannot reconstitute BCR function in Zap-70(+)BLNK(-) B cells. This could be attributable to inability of SLP-76 to be recruited into glycolipid-enriched microdomains (GEMs) after antigen receptor cross-linking. Supporting this idea, the BCR function was restored when a membrane-associated SLP-76 chimera was enforcedly localized to GEMs. Moreover, we demonstrate that addition of both linker for activation of T cells (LAT) and Grb2-related adaptor downstream of Shc (Gads) to SLP-76 allow SLP-76 to be recruited into GEMs, whereby the BCR function is reconstituted. The Gads function was able to be replaced by overexpression of Grb2. In contrast to SLP-76, BLNK did not require Grb2 families for its recruitment to GEMs. Hence, these data suggest a functional overlap between BLNK and SLP-76, while emphasizing the difference in requirement for additional adaptor molecules in their targeting to GEMs.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Cutting edge: essential role of phospholipase C-gamma 2 in B cell development and function.

Cross-linking of the B cell Ag receptor (BCR) induces the tyrosine phosphorylation of multiple cellular substrates, including phospholipase C (PLC)-gamma 2, which is involved in the activation of the phosphatidylinositol pathway. To assess the importance of PLC-gamma 2 in murine lymphopoiesis, the PLC-gamma 2 gene was inducibly ablated by using IFN-regulated Cre recombinase. Mice with a neonatally induced loss of PLC-gamma 2 function displayed reduced numbers of mature conventional B cells and peritoneal B1 cells and defective responses in vitro to BCR stimulation and in vivo to immunization with thymus-independent type II Ags. In contrast, T cell development and TCR-mediated proliferation were normal. Taken together, PLC-gamma 2 is a critical component of BCR signaling pathways and is required to promote B cell development.

Animals↗