Novel human brain cDNA encoding a 34,000 Mr protein n-chimaerin, related to both the regulatory domain of protein kinase C and BCR, the product of the breakpoint cluster region gene

Hall, Christine; Monfries, Clinton; Smith, Paul; Lim, Hong Hwa; Kozma, Robert; Ahmed, Sohail; Vanniasingham, Vasanthi M.; Leung, Thomas; Lim, Louis

doi:10.1016/0022-2836(90)90006-8

Cited by 167 publications

(103 citation statements)

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“…We had previously reported an increase in PKC binding sites using 3 H-phorbol dibutyrate as the ligand in the cytosol but not in the membrane fraction of platelets from unipolar patients (Pandey et al 1998). The reason for this discrepancy is not clear, but it could have various explanations; for exampe, some reports suggest that 3 H-PDBU Phorbol dibutyrate also binds to receptors other than PKC, including n-chimerin and Unc-13 (Hall et al 1990;Wilkinson and Hallam 1994). Therefore, it is possible that the increased binding observed by us in the cytosol fraction of platelets of unipolar patients may be due to increased binding to sites other than PKC.…”

Section: Discussionmentioning

confidence: 97%

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Pandey

Dwivedi

SridharaRao

et al. 2002

Neuropsychopharmacology

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Phospholipase C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide (PI) signaling system. To examine if the abnormalities observed in the PIdrolysis of the substrate, phosphatidyl inositol 4,5-bisphosphate (PIP 2 ), by the enzyme phospholipase C (PLC), resulting in the formation of two second messengers, inositol 1,4,5-trisphophate (IP 3 ) and diacylglycerol (DAG) (Berridge and Irvine 1989). IP 3 stimulates the release of intracellular calcium from the endoplasmic reticulum, and DAG stimulates the enzyme protein kinase C (PKC) (Nishizuka 1992), which is one of the major intracellular mediators of signals generated by the stimulation of cell surface receptors.Several studies indicate abnormalities of the PI signaling system in patients with unipolar or bipolar disorders. It has been reported that the hydrolysis of PIP 2 by several agonists, such as sodium fluoride (NaF) and GTP ␥ S, is altered in the postmortem brain of depressed Pacheco et al. 1996). PI signal transduction determined by serotonin (5HT)-, thrombin-, and NaF-stimulated IP formation has also been reported to be increased in platelets of depressed patients (Mikuni et al. 1991;Karege et al. 1996). These abnormalities may be related to abnormalities in receptors, such as 5HT 2A , 5HT 2C , muscarinic M 1 and M 2 , or ␣ 2 adrenergic receptors linked to the PI signaling system or to abnormal levels of substrates, such as PIP 2 , or to components of the signaling cascade, such as G-proteins, PKC, or PLC. Abnormalities in 5HT 2A (Pandey et al. 1995), ␣ 2 adrenergic receptors (Pandey et al. 1990), G-proteins (Garcia-Sevilla et al. 1997Karege et al. 1998;Gurguis et al. 1999), and levels of PIP 2 , a substrate for PI-PLC (Brown et al. 1993;Soares and Mallinger 1996;Soares et al. 1999), have been reported in platelets of unipolar and/or bipolar patients. PLC and PKC are two crucial components of the PI signaling system. Both PKC and PLC have been shown to be involved in a variety of physiological functions, such as synthesis, release, and reuptake of neurotransmitters, neuronal development, transcription, longterm potentiation (LTP), and behavioral responses (Nishizuka 1992). Although the role of PLC in affective disorders has not been fully investigated, some studies have shown abnormalities of PLC in depression and suicide Pandey et al. 1999). On the other hand, very few studies have examined the role of PKC in bipolar or unipolar disorders, although PKC has been implicated in the pathophysiology of bipolar disorders. For example, it has been reported that PKC activity as well as translocation of PKC from cytosol to membrane are increased in platelets of bipolar patients and that lithium treatment alters the activity of PKC in platelets (Friedman et al. 1993;Wang et al. 1999). Further evidence for the involvement of PKC in bipolar disorders is derived from observations that lithium exerts significant effects on PKC in a number of cell systems, including central nervous system (CNS) (Manji et al. 1993(Manji et al. , 1995Manji ...

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Section: Discussionmentioning

confidence: 97%

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Pandey

Dwivedi

SridharaRao

et al. 2002

Neuropsychopharmacology

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“…A cytosolic protein PKC has been shown to play an important role in platelet aggregation by pharmacological experiments using cell-permeable small compounds of inhibitors and stimulators such as phorbol esters (16,17). However, the results obtained from such experiments appear somewhat indirect because the specificity of inhibitors is not absolutely strict and important signaling molecules containing the phorbol ester-binding C1 domain other than PKC have been recently identified such as Ras-guanyl nucleotide-releasing protein (11,12) and chimerin (13,14). Munc13-1 present in the presynapse also contains the C1 domain (38), and it has very recently been demonstrated that the effect of phorbol ester in the neurotransmitter release is through Munc13-1 (39).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Ras-guanyl nucleotide-releasing protein (11,12) contains the C1 domain at its C terminus and acts as a stimulator for small GTPase Ras involved in the regulation of cell growth. Chimerin (13,14) also contains a C1 domain and acts as a GTPase-activating protein of small GTPase Rac involved in the regulation of cytoskeletal reorganization. Thus, the effects of phorbol esters could be through multiple pathways.…”

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confidence: 99%

Direct Demonstration of Involvement of Protein Kinase Cα in the Ca2+-induced Platelet Aggregation

Tabuchi¹,

Yoshioka²,

Higashi³

et al. 2003

Journal of Biological Chemistry

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Platelets play critical roles in hemostasis and thrombosis through their aggregation following activation of integrin ␣ IIb ␤ 3 . However, the molecular mechanism of the integrin activation inside platelets remains largely unknown. Pharmacological experiments have demonstrated that protein kinase C (PKC) plays an important role in platelet aggregation. Because PKC inhibitors can have multiple substrates and given that non-PKC-phorbol ester-binding signaling molecules have been demonstrated to play important roles, the precise involvement of PKC in cellular functions requires re-evaluation. Here, we have established an assay for analyzing the Ca 2؉ -induced aggregation of permeabilized platelets. The aggregation of platelets was inhibited by the addition of the arginine-glycine-aspartate-serine peptide, an integrin-binding peptide inhibitor of ␣ IIb ␤ 3 , suggesting that the aggregation was mediated by the integrin. The aggregation was also dependent on exogenous ATP and platelet cytosol, indicating the existence of essential cytosolic factors required for the aggregation. To examine the role of PKC in the aggregation assay, we immunodepleted PKC␣ and ␤ from the cytosol. The PKC-depleted cytosol lost the aggregation-supporting activity, which was recovered by the addition of purified PKC␣. Furthermore, the addition of purified PKC␣ in the absence of cytosol did not support the aggregation, whereas the cytosol containing less PKC supported it efficiently, suggesting that additional factors besides PKC would also be required. Thus, we directly demonstrated that PKC␣ is involved in the regulation of Ca 2؉ -induced platelet aggregation.Platelets play critical roles in hemostasis and thrombosis through aggregation following activation of integrin ␣ IIb ␤ 3 (1-3). Although ␣ IIb ␤ 3 of platelets in the resting stage does not bind fibrinogen or von Willebrand factors (vWF), 1 the activation of platelets results in conformation changes, which allow ␣ IIb ␤ 3 to bind these ligands (1-3). When fibrinogen or vWF binds to ␣ IIb ␤ 3 , the ligand-occupied integrin signals downstream to stabilize platelet aggregation through reorganization of the actin cytoskeletal network and the release of bioactive substances stored in the granules (1-3). Thus, the process of platelet activation and aggregation consists of a series of orchestrated responses (1-3). However, the molecular mechanisms that underlie this process remain unclear because it is difficult to use molecular biology and biochemistry in platelets that do not synthesize new proteins. To overcome this difficulty, semi-intact assays using permeabilized platelets have been established for the study of granule secretion (4 -8). Although some semi-intact aggregation assays have now been developed, it has been difficult to demonstrate a cytosol dependence in these experiments (8).Protein kinase C (PKC) family members are important signaling molecules regulating many cellular functions (9, 10). Among the family members, conventional PKCs (cPKC), which include PKC␣, ␤I, ␤II, and ␥...

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“…Eukaryotic cells contain five types of typical DAG-binding proteins, including certain isoforms of diacylglycerol kinases (DAGK; Kanoh et al, 1993), protein kinase D (PKD; Valverde et al, 1994), chimerins (Hall et al, 1990), RasGRP (Ebinu et al, 1998), and munc 13 (Betz et al, 1997). The increase in DAG-regulated protein number and functions suggests a high degree of complexity in the signaling pathways activated by this lipid.…”

Section: Introductionmentioning

confidence: 99%

Diacylglycerol-dependent Binding Recruits PKCθ and RasGRP1 C1 Domains to Specific Subcellular Localizations in Living T Lymphocytes

Carrasco

Mérida

2004

MBoC

127

132

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Diacylglycerol (DAG) signaling relies on the presence of conserved domain 1 (C1) in its target proteins. Phospholipase C-dependent generation of DAG after T cell receptor (TCR) triggering is essential for the correct immune response onset. Accordingly, two C1-containing proteins expressed in T lymphocytes, Ras guanyl nucleotide-releasing protein1 (Ras-GRP1) and protein kinase C (PKC), were shown to be fundamental for T-cell activation and proliferation. Although containing the same regulatory domain, they are proposed to relocate to distinct subcellular locations in response to TCR triggering. Here we studied intracellular localization of RasGRP1 and PKC C1 domains in living Jurkat T cells. The results demonstrate that, in the absence of significant primary sequence differences, the C1 domains of these proteins show specific localization within the cell and distinct responses to pharmacological stimulation and TCR triggering. These differences help explain the divergent localization and distinct functional roles of the full-length proteins, which contains them. The properties of these DAG-binding modules allow their characterization as functional markers that discriminate between DAG pools. Finally, we show that by binding to different diacylglycerol forms, overexpression of distinct C1 modules can attenuate DAG-dependent signals originating from the plasma or internal membranes. This is shown by analyzing the contribution of these two lipid pools to PLC-dependent Ras activation in response to TCR triggering.

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Novel human brain cDNA encoding a 34,000 Mr protein n-chimaerin, related to both the regulatory domain of protein kinase C and BCR, the product of the breakpoint cluster region gene

Cited by 167 publications

References 20 publications

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Direct Demonstration of Involvement of Protein Kinase Cα in the Ca2+-induced Platelet Aggregation

Diacylglycerol-dependent Binding Recruits PKCθ and RasGRP1 C1 Domains to Specific Subcellular Localizations in Living T Lymphocytes

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