Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein phosphorylation is considered an early cellular mechanism of signal transduction by surface immunoglobulins (sIg) and other receptors of B cells. Using intact human peripheral blood B cells of young subjects labeled with orthophosphate, increased phosphorylation levels of serine/threonine and tyrosine substrates were demonstrated on indicator phosphoproteins corresponding to the CD20 isoforms and microtubule-associated protein 2 kinase after cross-linking sIg and costimulation with phorbol diesters. By contrast, stimulated B cells from certain elderly subjects displayed substantial alterations in the phosphorylation patterns of serine/threonine or tyrosine indicator phosphoproteins. Also, age-related impairments in sIg stimulated mobilization of cytosolic protein kinase C (PKC) enzymatic activity and in cytosolic calcium [Ca2+]i responses of B cells were observed with the altered phosphorylation reactions. Comparison of the substrate phosphorylation profiles to the proliferative responses of stimulated B cells from individual elderly subjects suggested a model of signal transduction in which differing stimuli have different dependencies on phosphorylation reactions. Diminished proliferative responses after sIg ligation coincided with decreased phosphorylations of either tyrosine or serine/threonine indicator substrates. However, the decreased proliferative responses of B cells from elderly subjects with substantial reductions of tyrosine phosphorylation after sIg ligation were enhanced by the direct stimulation of serine/threonine kinase activity with phorbol diesters or CD40 ligation. Experiments with kinase inhibitors evaluated the relative dependency of different B cell stimuli on tyrosine and serine/threonine phosphorylation reactions. The proliferative responses of normal B cells to sIg ligation were quite sensitive to the tyrosine kinase inhibitor genistein whereas those observed following costimulations with phorbol diesters or CD40 ligation were more resistant. However, treatment of B cells with H7, an inhibitor of PKC activity, led to a more uniform reduction of B-cell responses after different stimuli. Results from RNase protection assays of c-myc expression also suggested that different B-cell stimuli might utilize distinct intracellular signaling pathways. Both the type of stimuli and mode of sIg ligation were important in determining the stimulated levels of c-myc mRNA expression. Thus, the current findings suggest that age-related defects are present in human B cell signaling pathways as reflected by tyrosine and serine/threonine phosphorylation reactions. Also, these age-related defects can coexist with altered mobilization of PKC enzymatic activity and with alterations in [Ca2+]i and proliferative responses.
Lymphokine Cytokine Res 1991 Dec
PMID:Signal transduction in human B cells during aging: alterations in stimulus-induced phosphorylations of tyrosine and serine/threonine substrates and in cytosolic calcium responsiveness. 180 9

The signal transducers and activators of transcription 1 (Stat1) are essential for the majority of interferon-gamma (IFN-gamma)-regulated gene expression. Phosphorylation of serine 727 in the transcription activation domain of Stat1 is induced in response to IFN-gamma for maximal transcription activity. In this report, we show that crosslinking of B cell antigen receptor (BCR) or T cell antigen receptor (TCR) can enhance S727 phosphorylation in Stat1 and result in increased expression of Stat1 target genes. We further demonstrate that this enhancement by BCR cross-linking involves the widely used secondary messenger Ca2+ and simultaneous activation of multiple serine kinase pathways. When cells are exposed to both IFN-gamma and a Ca2+ fluxing reagent, the level of S727 phosphorylation is enhanced, resulting in increased transcription activation of Stat1 target genes. We directly demonstrate that the biochemical function of phospho-Ser-727 is to enhance the recruitment of transcription coactivator CBP/p300 to the promoters of Stat1 target genes. Furthermore, we show that both the p38 mitogen-activated protein kinase (MAPK) and the Ca(2+)/calmodulin-dependent kinase (CaMKII) are activated in response to BCR signaling to converge on Stat1 S727 for maximal gene expression. These studies demonstrate that a wide variety of noncytokine signaling pathways can modulate cytokine signaling through modulation of Stat1 serine phosphorylation.
J Interferon Cytokine Res 2005 Feb
PMID:B cell antigen receptor signaling enhances IFN-gamma-induced Stat1 target gene expression through calcium mobilization and activation of multiple serine kinase pathways. 1569 32

The molecular pathways involved in the cellular response to interferon (IFN)gamma have been the focus of much research effort due to their importance in host defense against infection and disease, as well as its potential as a therapeutic agent. The discovery of the JAK-STAT signaling pathway greatly enhanced our understanding of the mechanism of IFNgamma-mediated gene transcription. However, in recent years it has become apparent that other pathways, including MAP kinase, PI3-K, CaMKII and NF-kappaB, either co-operate with or act in parallel to JAK-STAT signaling to regulate the many facets of IFNgamma biology in a gene- and cell type-specific manner. The complex interactions between JAK/STAT and alternate pathways and the impact of these signaling networks on the biological responses to IFNgamma are beginning to be understood. This review summarizes and appraises current advances in our understanding of these complex interactions, their specificity and proposed biological outcomes.
Cytokine Growth Factor Rev
PMID:IFNgamma signaling-does it mean JAK-STAT? 1892 2

Airway inflammation leads to increased intracellular Ca(2+) ([Ca(2+)](i)) levels in airway smooth muscle (ASM) cells. Sarcoplasmic reticulum Ca(2+) release and reuptake are key components of ASM [Ca(2+)](i) regulation. Ca(2+) reuptake occurs via sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA) and is regulated by the inhibitory protein phospholamban (PLB) in many cell types. In human ASM, we tested the hypothesis that inflammation increases PLB, thus inhibiting SERCA function, and leading to maintained [Ca(2+)](i) levels. Surprisingly, we found that human ASM does not express PLB protein (although mRNA is detectable). Overnight exposure to the proinflammatory cytokines TNFalpha and IL-13 did not induce PLB expression, raising the issue of how SERCA is regulated. We then found that direct SERCA phosphorylation (via CaMKII) occurs in human ASM. In fura-2-loaded human ASM cells, we found that the CaMKII antagonist KN-93 significantly slowed the rate of fall of [Ca(2+)](i) transients induced by ACh or bradykinin (in zero extracellular Ca(2+)), suggesting a role for CaMKII-mediated SERCA regulation. SERCA expression was decreased by cytokine exposure, and the rate of fall of [Ca(2+)](i) transients was slowed in cells exposed to TNFalpha and IL-13. Cytokine effects on Ca(2+) reuptake were unaffected by additional exposure to KN-93. These data indicate that in human ASM, SERCA is regulated by mechanisms such as CaMKII and that airway inflammation maintains [Ca(2+)](i) levels by decreasing SERCA expression and slowing Ca(2+) reuptake.
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PMID:Effect of proinflammatory cytokines on regulation of sarcoplasmic reticulum Ca2+ reuptake in human airway smooth muscle. 1978 41