Amnon Altman

..PKC acts solely within the canonical pathway to activate NF-kappaB, and PKC deficiency impacts upon p100/p52 processing in a manner that is independent of NF-kappaB-induced kinase...

..This represents a novel mechanism for the active immune synapse recruitment and activation of a phosphatase in TCR signaling...

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..Among these, the nuclear factor-kappaB (NF-kappaB) signaling cascade appears to be the most critical target of PKCtheta in the T-cell receptor/CD28 costimulatory pathway that leads to T-cell activation...

..Moreover, they identify Tec as a key point downstream of PKCtheta, where TCR- and PKCtheta-induced signaling pathways, leading to AP-1 versus NF-kappaB activation, diverge in T cells...

..Additional work is required to identify the immediate targets of PKCtheta and its immune functions in vivo. This work is likely to validate PKCtheta as an attractive drug target...

..Resolution of these questions could open the way to the development of selective PKC theta inhibitors, which may have therapeutic potential in immunological diseases and in cancer...

..Thus, Vav1 is selectively required for IL-4 and c-Maf expression, a requirement reflecting, at least in part, the dependence of c-Maf expression on Ca2+/NFAT signaling...

..Therefore, tyrosine-phosphorylation-mediated relocalization of SLAT to the site of antigen recognition is required for SLAT to exert its pivotal role in NFAT-dependent CD4(+) T cell differentiation...

..Thus, SLAT is required for thymic DN1 cell expansion, T cell activation, and Th1 and Th2 inflammatory responses...

..Altogether, our data show that TCR-induced association of Vav3 with SLP-76 is required for its membrane/IS localization and function...

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..Future work will aim to dissect the interacting partners of SLAT and may thus shed light on the poorly understood events that coordinate and link actin cytoskeleton reorganization to Ca2+ signaling and gene transcription in T cells...

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..These results define SPAK as a substrate and target of PKCtheta in a TCR/CD28-induced signaling pathway leading selectively to AP-1 (but not NF-kappaB) activation...

..These data provide evidence of a pivotal role for PKCtheta in the generation and effector function of autoimmune Th1 cells...

..These results provide evidence that a nonconventional PI3-K- and Vav-dependent pathway mediates the selective membrane recruitment and, possibly, activation of PKCtheta in T cells...

..Therefore, our study establishes T cell-expressed SLAT/Def6 as a pivotal positive regulator of Th17 inflammatory responses and, thus, essential in controlling autoimmune and inflammatory diseases...

..Engineered aAPC may have immediate application for basic and clinical immunology studies pertaining to modulation of T cells ex vivo...

..Furthermore, LAT palmitoylation functions primarily as a sorting signal required for its PM transport...

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..In contrast, a point mutation in the SH2 domain of Vav1 abolished this synergistic effect. Therefore, our results suggest a new regulatory effect of Vav1 in T cell spreading, which is independent of its guanine exchange factor activity...

..Thus, Vav1 is a critical regulator of a PI3K/Akt/FOXO1 pathway, which controls T cell cycle progression and proliferation...

..Therefore, PKCtheta is a critical enzyme that regulates T cell function at multiple stages, and it represents an attractive drug target for allergic and autoimmune diseases...

..Thus, by recruiting TCR-related intracellular molecules into the TRAF2 complex, OX40 provides the T cell with a high level of NF-κB activity needed for longevity...

..Therefore, given the essential role of PKCtheta in IL-2 production, IL-2 gene regulation by PKCtheta could also be of therapeutic interest...

..These data suggest that PKCtheta can play roles in aspects of both Th2 and Th1 responses, but lung inflammation induced by Th2 cells is more dependent on this protein kinase than lung inflammation induced by Th1 cells...

..Consistent with these results, pharmacological inhibition of ZAP-70 also induced Th2 skewing. Thus, SLAT is a protein which plays a role in Th2 development and/or activation, perhaps by interfering with ZAP-70 signaling...

..Reversible protein palmitoylation will likely prove to be an important posttranslational mechanism that regulates cellular responses, similar to protein phosphorylation and ubiquitination...

..The term 'Ariadne's thread' is used to describe the understanding of complex issues. Immunologists attending the 5th Leukocyte Signal Transduction Workshop discussed the Ariadne's thread woven about intracellular signaling pathways...

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..Altogether, these findings demonstrate that PKC-theta is an interferon-inducible kinase and strongly suggest that it plays an important role in the generation of interferon-responses in T-cells...

..Together, these observations lead us to believe that the difference of a single amino acid, which affects Grb2 binding ability, may define a functional difference between the CD28- and ICOS-mediated costimulatory signals...

..The selective expression of PKC theta in T cells and its essential role in mature T cell activation establish it as an attractive drug target for immunosuppression in transplantation and autoimmune diseases...

..Vav1 cells. Finally, evidence is presented to suggest that the alternative Vav family members, Vav-2 and Vav-3, are activated during TCR ligation, and partially compensate for the loss of Vav-1 in Jurkat T cells...

..Vav activates the IFN-gamma promoter via upregulation of AP-1-binding through a Rac1/JNK pathway...

..Finally, evidence was provided that 3BP2 functionally cooperates with Vav proteins and Rho GTPases to activate NFATs. Our results show that 3BP2 may regulate BCR-mediated gene activation through Vav proteins...

..Collectively, these results show that PKC has a unique membrane binding and activation mechanism that may account for its subcellular targeting properties...

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..Inhibition of PKCdelta activity with rottlerin blocked the increase in SPAK kinase activity. The results indicate that PKCdelta acts upstream of SPAK to increase activity of NKCC1 during hyperosmotic stress...

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..They offer the potential for developing novel therapeutic strategies, which may be useful for modulating CD28 costimulation in disease. ..

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..These studies will characterize a novel, multifunctional TCR-proximal protein. ..

..abstract_text> ..

..These studies will characterize a novel, multifunctional TCR-proximal protein. ..

..Understanding of these pathways is likely to establish a more rational basis for the use of PKC? as a drug target in autoimmune and allergic diseases, and in T cell leukemias/lymphomas ..

..These studies will characterize a novel, multifunctional TCR-proximal protein. ..

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..Understanding the roles of PKC and TPKs in T cell activation may lead to rational design of pharmacological approaches aimed at correcting abnormal T cell responses resulting from defective signaling...

..The proposed studies are intended to fill some important gaps in our understanding of signal transduction through the TCR. ..

..Understanding of these pathways is likely to establish a more rational basis for the use of PKC? as a drug target in autoimmune and allergic diseases, and in T cell leukemias/lymphomas ..