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)

Regulators of G protein signaling (RGS) are a family of proteins that attenuate the activity of the trimeric G proteins. RGS proteins act as GTPase-activating proteins (GAPs) for the alpha subunits of several trimeric G proteins, much like the GAPs that regulate the activity of monomeric G proteins such as Ras. RGS proteins have been cloned from many eukaryotes, and those whose biochemical activity has been characterized regulate the members of the Gi family of G proteins; some forms can also act on Gq proteins. In an ongoing effort to elucidate the role of Gzalpha in cell signaling, the yeast two-hybrid system was employed to identify proteins that could interact with a mutationally activated form of Gzalpha. A novel RGS, termed RGSZ1, was identified that is most closely related to two existing RGS proteins termed RetRGS1 and GAIP. Northern blot analysis revealed that expression of RGSZ1 was limited to brain, and expression was particularly high in the caudate nucleus. Biochemical characterization of recombinant RGSZ1 protein revealed that RGSZ1 was indeed a GAP and, most significantly, showed a marked preference for Gzalpha over other members of the Gialpha family. Phosphorylation of Gzalpha by protein kinase C, an event known to occur in cells and that was previously shown to influence alpha-betagamma interactions of Gz, rendered the G protein much less susceptible to RGSZ1 action.
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PMID:RGSZ1, a Gz-selective regulator of G protein signaling whose action is sensitive to the phosphorylation state of Gzalpha. 974 79

We cloned the cDNA for human RGSZ1, the major Gz-selective GTPase-activating protein (GAP) in brain (Wang, J., Tu, Y., Woodson, J., Song, X., and Ross, E. M. (1997) J. Biol. Chem. 272, 5732-5740) and a member of the RGS family of G protein GAPs. Its sequence is 83% identical to RET-RGS1 (except its N-terminal extension) and 56% identical to GAIP. Purified, recombinant RGSZ1, RET-RGS1, and GAIP each accelerated the hydrolysis of Galphaz-GTP over 400-fold with Km values of approximately 2 nM. RGSZ1 was 100-fold selective for Galphaz over Galphai, unusually specific among RGS proteins. Other enzymological properties of RGSZ1, brain Gz GAP, and RET-RGS1 were identical; GAIP differed only in Mg2+ dependence and in its slightly lower selectivity for Galphaz. RGSZ1, RET-RGS1, and GAIP thus define a subfamily of Gz GAPs within the RGS proteins. RGSZ1 has no obvious membrane-spanning region but is tightly membrane-bound in brain. Its regulatory activity in membranes depends on stable bilayer association. When co-reconstituted into phospholipid vesicles with Gz and m2 muscarinic receptors, RGSZ1 increased agonist-stimulated GTPase >15-fold with EC50 <12 nM, but RGSZ1 added to the vesicle suspension was <0.1% as active. RGSZ1, RET-RGS1, and GAIP share a cysteine string sequence, perhaps targeting them to secretory vesicles and allowing them to participate in the proposed control of secretion by Gz. Phosphorylation of Galphaz by protein kinase C inhibited the GAP activity of RGSZ1 and other RGS proteins, providing a mechanism for potentiation of Gz signaling by protein kinase C.
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PMID:RGSZ1, a Gz-selective RGS protein in brain. Structure, membrane association, regulation by Galphaz phosphorylation, and relationship to a Gz gtpase-activating protein subfamily. 974 80

Mitogen-activated protein (MAP) kinase family members, including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase ( JNK), and p38 MAP kinase, have been implicated in coupling the B cell antigen receptor (BCR) to transcriptional responses. However, the mechanisms that lead to the activation of these MAP kinase family members have been poorly elucidated. Here we demonstrate that the BCR-induced ERK activation is reduced by loss of Grb2 or expression of a dominant-negative form of Ras, RasN17, whereas this response is not affected by loss of Shc. The inhibition of the ERK response was also observed in phospholipase C (PLC)-gamma2-deficient DT40 B cells, and expression of RasN17 in the PLC-gamma2-deficient cells completely abrogated the ERK activation. The PLC-gamma2 dependency of ERK activation was most likely due to protein kinase C (PKC) activation rather than calcium mobilization, since loss of inositol 1,4,5-trisphosphate receptors did not affect ERK activation. Similar to cooperation of Ras with PKC activation in ERK response, both PLC-gamma2-dependent signal and GTPase are required for BCR-induced JNK and p38 responses. JNK response is dependent on Rac1 and calcium mobilization, whereas p38 response requires Rac1 and PKC activation.
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PMID:Involvement of guanosine triphosphatases and phospholipase C-gamma2 in extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase activation by the B cell antigen receptor. 976 8

In neuronal cells, activation of a certain heterotrimeric G protein-coupled receptor causes neurite retraction and cell rounding via the small GTPase Rho. However, the specific heterotrimeric G proteins that mediate Rho-dependent neurite retraction and cell rounding have not yet been identified. Here we investigated the effects of expression of constitutively active Galpha subunits on the morphology of differentiated PC12 cells. Expression of GTPase-deficient Galpha12, Galpha13, and Galphaq, but not Galphai2, caused neurite retraction and cell rounding in differentiated PC12 cells. These morphological changes induced by Galpha12, Galpha13, and Galphaq were completely inhibited by C3 exoenzyme, which specifically ADP-ribosylates and inactivates Rho. The tyrosine kinase inhibitor tyrphostin A25 blocked the neurite retraction and cell rounding induced by Galpha13 and Galphaq. However, tyrphostin A25 failed to inhibit the Galpha12-induced neuronal morphological changes. On the other hand, inhibition of protein kinase C or elimination of extracellular Ca2+ blocked the neurite retraction and cell rounding induced by Galphaq, whereas the morphological effects of Galpha12 and Galpha13 did not require activation of protein kinase C and extracellular Ca2+. These results demonstrate that activation of Galpha12, Galpha13, and Galphaq induces Rho-dependent morphological changes in PC12 cells through different signaling pathways.
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PMID:Constitutively active Galpha12, Galpha13, and Galphaq induce Rho-dependent neurite retraction through different signaling pathways. 978 65

Regulators of G protein signaling (RGS) proteins serve as potent GTPase-activating proteins for the heterotrimeric G proteins alphai/o and aq/11. This study describes the immunohistochemical distribution of RGS7 throughout the adult rat brain and its cellular colocalization with Galphaq/11, an important G protein-coupled receptor signal transducer for phospholipase Cbeta-mediated activity. In general, both RGS7 and Galphaq/11 displayed a heterogeneous and overlapping regional distribution. RGS7 immunoreactivity was observed in cortical layers I-VI, being most intense in the neuropil of layer I. In the hippocampal formation, RGS7 immunoreactivity was concentrated in the strata oriens, strata radiatum, mossy fibers, and polymorphic cells, with faint to nondetectable immunolabeling within the dentate gyrus granule cells and CA1-CA3 subfield pyramidal cells. Numerous diencephalic and brainstem nuclei also displayed dense RGS7 immunostaining. Dual immunofluorescence labeling studies with the two protein-specific antibodies indicated a cellular selectivity in the colocalization between RGS7 and Galphaq/11 within many discrete brain regions, such as the superficial cortical layer I, hilus area of the hippocampal formation, and cerebellar Golgi cells. To assess the ability of Galphaq/11-mediated signaling pathways to modulate dynamically RGS expression, primary cortical neuronal cultures were incubated with phorbol 12,13-dibutyrate, a selective protein kinase C activator. A time-dependent increase in levels of mRNA for RGS7, but not RGS4, was observed. Our results provide novel information on the region- and cell-specific pattern of distribution of RGS7 with the transmembrane signal transducer, Galphaq/11. We also describe a possible RGS7-selective neuronal feedback adaptation on Galphaq/11-mediated pathway function, which may play an important role in signaling specificity in the brain.
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PMID:Immunohistochemical distribution of RGS7 protein and cellular selectivity in colocalizing with Galphaq proteins in the adult rat brain. 988 68

Recent evidence demonstrates that the alpha subunits of some heterotrimeric GTP-binding proteins (G proteins) are subject to modification by protein kinase C (PKC). For the family of G proteins that activate the phospholipase C/inositol trisphosphate/calcium/PKC pathway, such modification could result in G protein autoregulation. To examine the potential regulation of members of the Galphaq family by PKC phosphorylation, we expressed the thyrotropin-releasing hormone (TRH) receptor in combination with Galphaq, Galpha11, Galpha14, Galpha15, or Galpha16 in Xenopus oocytes and examined the regulation of signaling by PKC activators and inhibitors. For Galpha16 and Galpha15, the two family members of hematopoietic lineage, PKC activators reduce both the magnitude and the time course of TRH-mediated responses; PKC inhibitors have the opposite effect. The PKC-mediated effects are evident in measurements of GTPase activity, suggesting that the regulation is occurring early in the signaling pathway. In vivo phosphorylation experiments demonstrate that Galpha16 is a substrate for PKC modification. By comparison, Galphaq is not phosphorylated by PKC in vivo, and oocytes expressing Galphaq are not functionally modulated by PKC. Repeated TRH stimulation of oocytes expressing Galpha16 mimics the effects of PKC activators, and this functional regulation is correlated with an increase in Galpha16 phosphorylation. A mutant Galpha16 with four consensus PKC phosphorylation sites removed is not phosphorylated in vivo, and TRH responses mediated through the mutant are not regulated by PKC. These results demonstrate that signaling involving hematopoietic G proteins is subject to PKC-mediated autoregulation, at least in part, by phosphorylation of the G protein alpha subunit.
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PMID:Functional regulation of Galpha16 by protein kinase C. 998 20

Cellular adhesions to other cells and to the extracellular matrix play crucial roles in the malignant progression of cancer. In this study, we investigated the role of protein kinase C (PKC) in the regulation of cell-substratum adhesion by the breast adenocarcinoma cell line MCF-7. A PKC activator, 12-O-tetradecanoylphorbol-l, 3-acetate (TPA), stimulated cell adhesion to laminin and collagen I in a dose-dependent manner over a 1- to 4-h interval. This enhanced adhesion was mediated by alpha2beta1 integrin, since both anti-alpha2 and anti-beta1 blocking antibodies each completely abrogated the TPA-induced adhesion. FACS analysis determined that TPA treatment does not change the cell surface expression of alpha2beta1 integrin over a 4-h time interval. However, alpha2beta1 levels were increased after 24 h of TPA treatment. Thus, the enhanced avidity of alpha2beta1-dependent cellular adhesion preceded the induction of alpha2beta1 cell surface expression. Northern blot analysis revealed that mRNA levels of both alpha2 and beta1 subunits were increased after exposure to TPA for 4 h, indicating that the induction of alpha2beta1 mRNA preceded that of its cell surface expression. This further suggested that the TPA-induced avidity of alpha2beta1 was independent of increased expression of alpha2beta1. Pretreatment of cells with the PKC inhibitor calphostin C partially antagonized the TPA-induced increase in expression of alpha2beta1 integrin expression and of alpha2beta1-mediated cellular adhesion. To identify a possible mechanism by which TPA could be acting to promote the rapid induction of alpha2beta1 adhesion, we treated the cells with the Rho-GTPase inhibitor Clostridium botulinumexotoxin C3. C3 inhibited TPA-induced adhesion to laminin and collagen I in a dose-dependant manner, suggesting a likely role for Rho in TPA-induced adhesion. Together, these results suggest that PKC can modulate the alpha2beta1-dependent adhesion of MCF-7 cells by two distinct mechanisms: altering the gene expression of integrins alpha2 and beta1 and altering the avidity of the alpha2beta1 integrin by a Rho-dependant mechanism.
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PMID:Activation of protein kinase C by phorbol esters modulates alpha2beta1 integrin on MCF-7 breast cancer cells. 1009 32

The transforming growth factor (TGF)-beta signal-transduction cascade from the cell membrane to the nuclear target is poorly characterised. Here we report that treatment with TGF-beta1 induces the levels of endogenous c-fos mRNA in Rat-2 fibroblast cells. In addition, by transient transfection analysis, TGF-beta1 was shown to stimulate c-fos serum response element (SRE)-driven reporter gene activity in a dose- and time-dependent manner, suggesting that SRE is one of the nuclear targets of TGF-beta1. To understand the signalling cascade by which TGF-beta1 mediates the transactivation of c-fos SRE, cells were either pre-treated with various inhibitors or co-transfected with expression plasmids encoding inhibitory proteins for Rho GTPase together with the SRE-luciferase reporter gene. Our results showed that an inhibition of protein kinase C (PKC) or RhoA selectively repressed the stimulation of c-fos SRE by TGF-beta1, implying the possible roles of PKC and RhoA GTPase in TGF-beta1-induced signalling to c-fos SRE.
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PMID:Involvement of protein kinase C and rho GTPase in the nuclear signalling pathway by transforming growth factor-beta1 in rat-2 fibroblast cells. 1020 47

Mouse guanylate-binding protein 3 (mGBP3) is a 71-kDa GTPase which belongs to GTP-binding protein family. The present study showed that the expression of mGBP3 transcript was readily induced in a dose dependent fashion in the macrophage cell line RAW264.7 treated with either interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS). The expression of mGBP3 protein was also apparent by 4 and 6 h after the treatment of cells with IFN-gamma (100 U/ml) or LPS (1 microgram/ml), and remained at plateau for at least 24 h. Cycloheximide (10 micrograms/ml) had no effect on the IFN-gamma- or LPS-induced mGBP3 expression, suggesting that the mGBP3 induction did not require further protein synthesis. Interestingly, a protein kinase C (PKC) inhibitor staurosporine (50 nM) abolished the induction of mGBP3 expression by LPS, but not by IFN-gamma. These findings suggest that mGBP3 may be involved in the macrophage activation process and both IFN-gamma and LPS induce the mGBP3 expression through distinct signal transduction pathways.
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PMID:Interferon-gamma and lipopolysaccharide induce mouse guanylate-binding protein 3 (mGBP3) expression in the murine macrophage cell line RAW264.7. 1023 May 2

The PKN family of PKC-related protein kinases constitutes the major Rho GTPase-associated protein kinase activities detected in mammalian tissues. However, the biological functions of these kinases are unknown. We have identified a closely related PKN homolog in Drosophila (Pkn) that binds specifically to GTP-activated Rho1 and Rac1 GTPases through distinct binding sites on Pkn. The interaction of Pkn with either of these GTPases results in increased kinase activity, suggesting that Pkn is a shared Rho/Rac effector target. Characterization of a loss-of-function mutant of Drosophila Pkn revealed that this kinase is required specifically for the epidermal cell shape changes during the morphogenetic process of dorsal closure of the developing embryo. Moreover, Pkn, as well as the Rho1 GTPase, mediate a pathway for cell shape changes in dorsal closure that is independent of the previously reported Rac GTPase-mediated Jun amino (N)-terminal kinase (JNK) cascade that regulates gene expression required for dorsal closure. Thus, it appears that distinct but coordinated Rho- and Rac-mediated signaling pathways regulate the cell shape changes required for dorsal closure and that Pkn provides a GTPase effector function for cell shape changes in vivo, which acts together with a Rac-JNK transcriptional pathway in the morphogenesis of the Drosophila embryo.
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PMID:The Drosophila Pkn protein kinase is a Rho/Rac effector target required for dorsal closure during embryogenesis. 1032 67


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