Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell surface expression of CD4, an invariant membrane glycoprotein, is characteristic of the MHC class II-restricted T cell helper/inducer subset. Although the specificity and restriction patterns of T lymphocytes are determined by the T cell receptor for antigen, CD4 might represent an additional "interaction" molecule that is required to strengthen the interaction between T cells, antigen, and antigen-presenting cells. In this manuscript, we have shown that the cell surface expression of CD4 is correlated with activation of T cells. Data presented in this paper have demonstrated, for the first time, that antigenic stimulation of human T cell clones caused a decrease in the expression of the CD4 marker (as well as to the CD3 marker) to about 50% of the constitutive level. As previously demonstrated, PMA caused modulation of CD4 and CD3, which suggested that phosphorylation by protein kinase C played a crucial role in the regulation of the expression of both markers. The parallel down-regulation of CD3 and CD4 after antigen stimulation suggested that both markers might be members of a multimolecular complex mediating T cell activation.
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PMID:Modulation of CD4 by antigenic activation. 310 Jun 38

Membrane assembly of the C5b-9 proteins on gel-filtered human platelets has been shown to initiate the nonlytic release of alpha-granule contents and expression of membrane prothrombinase sites, suggesting cellular activation by these ostensibly cytolytic plasma proteins (Wiedmer, T., Esmon, C. T., and Sims, P. J. (1986) J. Biol. Chem. 261, 14587-14592). We now examine the mechanism of the C5b-9-induced release reaction. The release of alpha-granule contents upon C5b-9 assembly is accompanied by expression of alpha-granule membrane glycoprotein 140 on the platelet surface, confirming that the complement-mediated release reaction occurs by secretory fusion of the alpha-granule with the plasma membrane. C5b-9 binding initiates the phosphorylation of both 40- and 20-kDa platelet proteins, indicative of activation of protein kinase C and myosin light chain kinase, respectively. Activation of cellular protein kinases under these conditions was not accompanied by the formation of inositol phosphates and was found to strictly depend upon extracellular Ca2+, suggesting that the platelet's secretory response to the C5b-9 proteins is triggered directly by the influx of Ca2+ across the plasma membrane. measurement of intracellular Ca2+ confirmed that elevation of this ion in the cytosol was strictly dependent upon increased plasma membrane permeability due to C5b-9 assembly and was not accompanied by mobilization of this ion from internal storage pools. The C5b-9-mediated secretory response was blocked by sphingosine, a potent inhibitor of protein kinase C, but was unaffected by the cyclooxygenase inhibitor indomethacin, suggesting that feedback (receptor-linked) by thromboxane is not required for platelet activation after C5b-9 insertion.
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PMID:Complement C5b-9-stimulated platelet secretion is associated with a Ca2+-initiated activation of cellular protein kinases. 311 83

The membrane glycoprotein CD4 is required for optimal antigen-mediated activation of CD4+ T cells restricted by class II molecules of the major histocompatibility complex (MHC). CD4 cross-linking by anti-CD4 antibodies or binding by human immunodeficiency virus (HIV) gp120 has been shown to inhibit antigen-dependent and -independent T cell activation, abrogating T cell proliferation, IL-2 synthesis and the increase in the intracellular calcium concentration. The molecular basis of these opposing phenomena is ill-defined. To characterize further the inhibitory role of the CD4 molecule, we investigated the effects of CD4 ligands on the transcription factors regulating the IL-2 gene enhancer and IL-2 synthesis. We first confirmed that pre-treatment of peripheral human CD4+ T lymphocytes by CD4 ligands, HIV gp120 or anti-CD4 monoclonal antibodies inhibited IL-2 production and cell proliferation, which was normally induced by an anti-CD3 antibody (UCHT1) plus a protein kinase C activator (PMA). Moreover, these CD4 ligands inhibited the proliferation and synthesis of IL-2 induced by activators bypassing membrane events, i.e. PMA and calcium ionophore, pointing to an active signaling pathway triggered by the CD4 molecule. Gp120 and anti-CD4 antibodies induced a specific, significant decrease in the binding activity of NF-AT, NF-kappa B and AP-1, three transcription factors regulating IL-2 gene enhancer activity, as demonstrated by electrophoretic mobility shift assays. Inhibition was similarly observed following cell activation by activators involving membrane events and those bypassing them. These results strongly suggest that the inhibition mediated by cross-linking of the CD4 molecule is at least partly due to negative signal down-regulating the availability of nuclear factors necessary for the regulation of IL-2 gene transcription.
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PMID:Interaction of HIV gp120 and anti-CD4 antibodies with the CD4 molecule on human CD4+ T cells inhibits the binding activity of NF-AT, NF-kappa B and AP-1, three nuclear factors regulating interleukin-2 gene enhancer activity. 795 56

Chemotaxis of the M27 variant of Lewis lung carcinoma to VGVAPG, an elastin-derived chemoattractant, is restricted by the basement membrane glycoprotein laminin. Laminin does not inhibit random migration of M27 tumor cells, nor does it inhibit M27 cell chemotaxis to a second chemotactic peptide, fMLF. The laminin sensitivity of VGVAPG chemotaxis appears to be independent of adhesion to laminin, and it is not due to competitive inhibition of VGVAPG receptor binding. Preincubation of M27 cells with laminin reduces the affinity of VGVAPG-specific binding without altering the number of available VGVAPG receptors. Reduced VGVAPG receptor affinity was previously observed: (a) a nonresponsive Lewis lung carcinoma variant, H59, expresses low-affinity VGVAPG binding and (b) maintenance of high-affinity VGVAPG receptors on M27 tumor cells is correlated with elevated protein kinase C activity in the particulate cell fraction (C. H. Blood and B. R. Zetter, J. Biol. Chem., 264: 10614-10620, 1989). The negative regulation of VGVAPG chemotaxis by laminin is consistent with these observations: laminin coordinately inhibits VGVAPG chemotaxis, reduces VGVAPG receptor affinity, and decreases protein kinase C activity in the particulate fraction of M27 cells. These parameters are not affected by a second glycoprotein, fibronectin. Anti-alpha 6 antibodies neutralize the laminin inhibition of both VGVAPG chemotaxis and protein kinase C activity. The results demonstrate that laminin can modulate cell behavior by regulating cell surface receptors for biologically active ligands.
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PMID:Laminin regulates a tumor cell chemotaxis receptor through the laminin-binding integrin subunit alpha 6. 838 19

Binding of the multimeric adhesive glycoprotein, von Willebrand Factor (vWF), to the platelet membrane glycoprotein (GP) Ib-IX-V complex mediates platelet adhesion and initiates signal transduction leading to platelet activation. Recently described viper venom proteins that bind to the GP Ib alpha-chain and inhibit vWF binding provide novel probes for studying receptor function. We have purified a 50-kDa form of alboaggregin from the white-lipped tree viper (Trimeresurus albolabris) and two 25-kDa proteins, CHH-A and CHH-B, from the timber rattlesnake (Crotalus horridus horridus) in addition to a previously described 25-kDa alboaggregin and echicetin. Complete or partial amino acid sequencing of CHH-A, CHH-B, and 50-kDa alboaggregin and cross-reactivity of these proteins with an anti-botrocetin antiserum confirmed that they were disulfide-linked heterodimers or higher multimers of the C-type lectin protein family. These proteins, together with 25-kDa alboaggregin and echicetin, specifically bound to GP Ib alpha within the N-terminal peptide domain, His-1-Glu-282, and inhibited vWF binding with comparable IC50 values (approximately 0.2 microgram/mL). However, cross-blocking studies between these structurally related proteins and anti-GP Ib alpha monoclonal antibodies demonstrated that the venom protein binding sites were not congruent. Further, the 50-kDa alboaggregin, but not the other venom proteins, potently induced platelet activation as assessed by dense granule serotonin release or elevation of cytosolic ionized calcium. Treatment of platelets with the 50-kDa alboaggregin was associated with activation of protein kinase C and tyrosine kinase(s), resulting in a platelet protein phosphorylation profile similar to that seen on shear-stress-induced vWF binding to platelets. These results suggest that the 50-kDa alboaggregin induces cytoplasmic signaling coincident with its binding to the GP Ib-IX-V complex and provides a potentially useful probe for studying the mechanism of vWF-dependent platelet activation.
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PMID:Binding of a novel 50-kilodalton alboaggregin from Trimeresurus albolabris and related viper venom proteins to the platelet membrane glycoprotein Ib-IX-V complex. Effect on platelet aggregation and glycoprotein Ib-mediated platelet activation. 882 1

A membrane glycoprotein CD4 functions as a co-receptor of a T lymphocyte. The co-receptor function has been attributed to a protein tyrosine kinase, p56lck, which is activated upon CD4 binding to MHC molecule. In this study, we present evidences that one of the pathways through which CD4 transmits its signal is cytoskeleton association of p56lck tyrosine kinase as well as CD4 itself. Cytoskeletal association of both proteins is inhibited by a tyrosine kinase inhibitor, genistein, indicating that tyrosine protein kinase activation is important for cytoskeletal association of CD4 and p56lck. Cytoskeletal association of these proteins by CD4 cross-linking is not affected by inhibitors of protein kinase C nor PI3-kinase. Taken together, these results suggest that CD4 cross-linking activates a tyrosine kinase which then induces the simultaneous association of CD4 and p56lck with cytoskeleton.
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PMID:Cross-linking of CD4 induces cytoskeletal association of CD4 and p56lck. 1076 57

To elucidate the function of M6a, which is a neuron-specific membrane glycoprotein of the brain and possesses putative phosphorylation sites for protein kinase C (PKC), we established rat M6a cDNA expression vector-transfected PC12 cells. These transfectants exhibited high susceptibilities to nerve growth factor (NGF) for neuronal differentiation. Interestingly, we found that Ca(2+) influx in these transfectants was significantly augmented by the treatment of NGF, but not epidermal growth factor (EGF), which stimulates PC12 cell growth. NGF-dependent augmentation of Ca(2+) influx was detected within 3h and severely inhibited by EGTA- and PKC-specific inhibitors. Anti-M6 antibody suppressed both NGF-triggered Ca(2+) influx and neuronal differentiation. These results support the idea that M6a implicates in neuronal differentiation as a novel Ca(2+) channel gated selectively by phosphorylation with PKC in the downstream of NGF signaling pathway.
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PMID:M6a acts as a nerve growth factor-gated Ca(2+) channel in neuronal differentiation. 1235 12

The rat ileal sodium-dependent bile acid transporter (Asbt) is a polytopic membrane glycoprotein, which is specifically expressed on the apical domain of the ileal brush-border membrane. In the present study, an essential 14-amino acid (aa 335-348) sorting signal was defined on the cytoplasmic tail of Asbt with two potential phosphorylation sites motifs for casein kinase II ((335)SFQE) and protein kinase C (PKC) ((339)TNK). Two-dimension NMR spectra analysis demonstrated that a tetramer, (340)NKGF, which overlaps with the potential PKC site within the 14-mer signal sequence, adopts a type I beta-turn conformation. Replacement of the potential phosphorylation residue Ser(335) and Thr(339) with alanine or deletion of either the 4 ((335)SFQE) or 10 aa (338-348, containing (339)TNKGF) from the C terminus of Asbt resulted in a significantly decreased initial bile acid transport activity and increased the basolateral distribution of the mutants by 2-3-fold compared with that of wild type Asbt. Deletion of the entire last 14 amino acids (335-348) from the C terminus of Asbt abolished the apical expression of the truncated Asbt. Moreover, replacement of the cytoplasmic tail of the liver basolateral membrane protein, Na(+)/taurocholate cotransporting polypeptide, with the 14-mer peptide tail of Asbt redirected the chimera to the apical domain. In contrast, a chimera consisting of the 14-mer peptide of Asbt fused with green fluorescent protein was expressed in an intracellular transport vesicle-like distribution in transfected Madin-Darby canine kidney and COS 7 cells. This suggests that the apical localization of the 14-mer peptide requires a membrane anchor to support proper targeting. The results from biological reagent treatment and low temperature shift (20 degrees C) suggests that Asbt follows a transport vesicle-mediated apical sorting pathway that is brefeldin A-sensitive and insensitive to protein glycosylation, monensin treatment, and low temperature shift.
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PMID:A 14-amino acid sequence with a beta-turn structure is required for apical membrane sorting of the rat ileal bile acid transporter. 1243 49

Platelet activation by thrombin plays a major role in the development of haemostasis and thrombosis. Thrombin activates human platelets by cleaving the N-terminal region of G-protein-coupled protease-activated receptors (PARs). On the other hand, the platelet membrane glycoprotein GPIb acts as a thrombin-binding site and promotes platelet activation by low thrombin concentrations. We present here new evidence in favour of a thrombin receptor function for GPIb. We have selected conditions in which thrombin-GPIb interactions were enhanced by thrombin immobilization. Activation was studied independently of PAR cleavage by using active-site-blocked thrombin. We show that immobilized, proteolytically inactive thrombin induces platelet adhesion and spreading, dense granule secretion and integrin alphaIIbbeta3-dependent platelet-platelet interactions. The pathway must be dependent on GPIb because it is deficient in platelets from a patient with Bernard Soulier syndrome and inhibited by a monoclonal antibody to GPIb (SZ2) or by an excess of glycocalicin. Secreted ADP plays a major role in GPIb-dependent thrombin-induced platelet activation which is, in addition, regulated by cAMP concentration. Thrombin-induced GPIb-dependent platelet activation leads to tyrosyl phosphorylation of several proteins. Inhibition of platelet-platelet interactions and protein tyrosine phosphorylations by inhibitors of phosphatidylinositol 3-kinases and protein kinase C implies that activation of the latter are important steps of the GPIb-coupled signalling pathway triggered by thrombin.
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PMID:Glycoprotein Ib-mediated platelet activation. A signalling pathway triggered by thrombin. 1284 29

Agglucetin, a tetrameric agglutination inducer from the Formosan pit viper, has been identified as a platelet membrane glycoprotein (GP) Ib agonist and directly agglutinated fixed-platelets in the absence of von Willebrand factor (vWf). Here, we resolved the complete cDNA sequences of agglucetin subunits (alpha(1), alpha(2), beta(1) and beta(2)) by molecular cloning. Each cloned cDNA encoding the leader peptide (23 residues) and the mature subunit (131/135/123/126 residues) shares a high degree of homology to each other and the C-type lectin-like GP Ib-binding proteins (BPs). Furthermore, agglucetin specifically caused platelet agglutination and surface exposure of integrin alpha(IIb)beta(3) with a GPIb-dependent manner in washed platelets, based on the observation that the enhanced expression of functional alpha(IIb)beta(3) was suppressed by a GPIb-cleaving metalloproteinase, crotalin. Pretreating platelets with staurosporine or BAPTA-AM also completely blocked the exposure of functional alpha(IIb)beta(3), suggesting that the activation of protein kinase C and intracellular calcium mobilization are involved in the GPIb-dependent signaling. In human platelet-rich plasma (PRP), agglucetin elicited sequential biphasic responses of platelet agglutination and aggregation in a GPIb- and alpha(IIb)beta(3)-dependent manner, respectively, implying that other cofactors may amplify platelet activation to trigger aggregation.
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PMID:A tetrameric glycoprotein Ib-binding protein, agglucetin, from Formosan pit viper: structure and interaction with human platelets. 1295 16


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