scholarly journals Direct Binding and Activation of Protein Kinase C Isoforms by Aldosterone and 17β-Estradiol

2007 ◽  
Vol 21 (11) ◽  
pp. 2637-2650 ◽  
Author(s):  
Rodrigo Alzamora ◽  
Laura R. Brown ◽  
Brian J. Harvey
Keyword(s):  
Estrogen Receptor ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Steroid Hormones ◽  
Molecular Mechanisms ◽  
Receptor Expression ◽  
C2 Domain ◽  
Kinase C ◽  
Direct Binding ◽  
17Β Estradiol

Abstract Protein kinase C (PKC) is a signal transduction protein that has been proposed to mediate rapid responses to steroid hormones. Previously, we have shown aldosterone directly activates PKCα whereas 17β-estradiol activates PKCα and PKCδ; however, neither the binding to PKCs nor the mechanism of action has been established. To determine the domains of PKCα and PKCδ involved in binding of aldosterone and 17β-estradiol, glutathione S-transferase fusion recombinant PKCα and PKCδ mutants were used to perform in vitro binding assays with [3H]aldosterone and [3H]17β-estradiol. 17β-Estradiol bound both PKCα and PKCδ but failed to bind PKC mutants lacking a C2 domain. Similarly, aldosterone bound only PKCα and mutants containing C2 domains. Thus, the C2 domain is critical for binding of these hormones. Binding affinities for aldosterone and 17β-estradiol were between 0.5–1.0 nM. Aldosterone and 17β-estradiol competed for binding to PKCα, suggesting they share the same binding site. Phorbol 12,13-dybutyrate did not compete with hormone binding; furthermore, they have an additive effect on PKC activity. EC50 for activation of PKCα and PKCδ by aldosterone and 17β-estradiol was approximately 0.5 nM. Immunoblot analysis using a phospho-PKC antibody revealed that upon binding, PKCα and PKCδ undergo autophosphorylation with an EC50 in the 0.5–1.0 nm range. 17β-Estradiol activated PKCα and PKCδ in estrogen receptor-positive and -negative breast cancer cells (MCF-7 and HCC-38, respectively), suggesting estrogen receptor expression is not required for 17β-estradiol-induced PKC activation. The present results provide first evidence for direct binding and activation of PKCα and PKCδ by steroid hormones and the molecular mechanisms involved.

Regulation of Scavenger Receptor Expression in Smooth Muscle Cells by Protein Kinase C

1997 ◽  
Vol 17 (5) ◽  
pp. 969-978 ◽  
Author(s):  
Michele Mietus-Snyder ◽  
Annabelle Friera ◽  
Christopher K. Glass ◽  
Robert E. Pitas
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Smooth Muscle Cells ◽  
Scavenger Receptor ◽  
Muscle Cells ◽  
Receptor Expression ◽  
Kinase C

scholarly journals Physiological Role for Phosphatidic Acid in the Translocation of the Novel Protein Kinase C Apl II in Aplysia Neurons

2008 ◽  
Vol 28 (15) ◽  
pp. 4719-4733 ◽  
Author(s):  
Carole A. Farah ◽  
Ikue Nagakura ◽  
Daniel Weatherill ◽  
Xiaotang Fan ◽  
Wayne S. Sossin
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phosphatidic Acid ◽  
Physiological Role ◽  
C2 Domain ◽  
The Novel ◽  
Physiological Conditions ◽  
Kinase C ◽  
Neuronal Membranes ◽  
Novel Protein

ABSTRACT In Aplysia californica, the serotonin-mediated translocation of protein kinase C (PKC) Apl II to neuronal membranes is important for synaptic plasticity. The orthologue of PKC Apl II, PKCε, has been reported to require phosphatidic acid (PA) in conjunction with diacylglycerol (DAG) for translocation. We find that PKC Apl II can be synergistically translocated to membranes by the combination of DAG and PA. We identify a mutation in the C1b domain (arginine 273 to histidine; PKC Apl II-R273H) that removes the effects of exogenous PA. In Aplysia neurons, the inhibition of endogenous PA production by 1-butanol inhibited the physiological translocation of PKC Apl II by serotonin in the cell body and at the synapse but not the translocation of PKC Apl II-R273H. The translocation of PKC Apl II-R273H in the absence of PA was explained by two additional effects of this mutation: (i) the mutation removed C2 domain-mediated inhibition, and (ii) the mutation decreased the concentration of DAG required for PKC Apl II translocation. We present a model in which, under physiological conditions, PA is important to activate the novel PKC Apl II both by synergizing with DAG and removing C2 domain-mediated inhibition.

Berberine reduces insulin resistance through protein kinase C–dependent up-regulation of insulin receptor expression

Metabolism ◽  
2009 ◽  
Vol 58 (1) ◽  
pp. 109-119 ◽  
Author(s):  
Wei-Jia Kong ◽  
Hao Zhang ◽  
Dan-Qing Song ◽  
Rong Xue ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Receptor Expression ◽  
Kinase C ◽  
Insulin Receptor Expression

Relationship between aldose reductase enzyme and the signaling pathway of protein kinase C in an in vitro diabetic retinopathy model

2020 ◽  
Vol 98 (4) ◽  
pp. 243-251
Author(s):  
Mutlu Sarikaya ◽  
Nuray Yazihan ◽  
Net Daş Evcimen
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Signaling Molecules ◽  
Protein Levels ◽  
Kinase C ◽  
The Relationship ◽  
And Oxidative Stress ◽  
Expression And Activity

Protein kinase C (PKC) and aldose reductase (AR) enzyme activities are increased in diabetes and complications are include retinopathy, nephropathy, and neuropathy. However, the relationship between PKC and AR and the underlying molecular mechanisms is still unclear. We aimed to evaluate the relationship between these two enzymes and clarify the underlying molecular mechanisms by the related signaling molecules. The effects of hyperglycemia and oxidative stress on AR and PKC enzymes and the signaling molecules such as nuclear factor-kappa B (NF-κB), inhibitor kappa B-alpha (IkB-α), total c-Jun, phospho c-Jun, and stress-activated protein kinases (SAPK)/Jun amino-terminal kinases (JNK) were evaluated in human retinal pigment epithelial cells (ARPE-19). AR, PKC protein levels, and related signaling molecules increased with hyperglycemia and oxidative stress. The AR inhibitor sorbinil decreased PKC expression and activity and all signaling molecule protein levels. Increased AR expression during hyperglycemia and oxidative stress was found to be correlated with the increase in PKC expression and activity in both conditions. Decreased expression and activity of PKC and the protein levels of related signaling molecules with the AR inhibitor sorbinil showed that AR enzyme may play a key role in the expression of PKC enzyme and oxidative stress during diabetes.

scholarly journals Protein Kinase C Signaling Mediates a Program of Cell Cycle Withdrawal in the Intestinal Epithelium

2000 ◽  
Vol 151 (4) ◽  
pp. 763-778 ◽  
Author(s):  
Mark R. Frey ◽  
Jennifer A. Clark ◽  
Olga Leontieva ◽  
Joshua M. Uronis ◽  
Adrian R. Black ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Intestinal Epithelium ◽  
Molecular Mechanisms ◽  
Model Systems ◽  
Intestinal Epithelial ◽  
Kinase C

Members of the protein kinase C (PKC) family of signal transduction molecules have been widely implicated in regulation of cell growth and differentiation, although the underlying molecular mechanisms involved remain poorly defined. Using combined in vitro and in vivo intestinal epithelial model systems, we demonstrate that PKC signaling can trigger a coordinated program of molecular events leading to cell cycle withdrawal into G0. PKC activation in the IEC-18 intestinal crypt cell line resulted in rapid downregulation of D-type cyclins and differential induction of p21waf1/cip1 and p27kip1, thus targeting all of the major G1/S cyclin-dependent kinase complexes. These events were associated with coordinated alterations in expression and phosphorylation of the pocket proteins p107, pRb, and p130 that drive cells to exit the cell cycle into G0 as indicated by concomitant downregulation of the DNA licensing factor cdc6. Manipulation of PKC isozyme levels in IEC-18 cells demonstrated that PKCα alone can trigger hallmark events of cell cycle withdrawal in intestinal epithelial cells. Notably, analysis of the developmental control of cell cycle regulatory molecules along the crypt–villus axis revealed that PKCα activation is appropriately positioned within intestinal crypts to trigger this program of cell cycle exit–specific events in situ. Together, these data point to PKCα as a key regulator of cell cycle withdrawal in the intestinal epithelium.

scholarly journals The C2 Domain and Altered ATP-Binding Loop Phosphorylation at Ser359Mediate the Redox-Dependent Increase in Protein Kinase C-δ Activity

2015 ◽  
Vol 35 (10) ◽  
pp. 1727-1740 ◽  
Author(s):  
Jianli Gong ◽  
Yongneng Yao ◽  
Pingbo Zhang ◽  
Barath Udayasuryan ◽  
Elena V. Komissarova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Kinase Domain ◽  
Cellular Growth ◽  
C2 Domain ◽  
Kinase C ◽  
High Level ◽  
Docking Interaction ◽  
Structural Determinant

The diverse roles of protein kinase C-δ (PKCδ) in cellular growth, survival, and injury have been attributed to stimulus-specific differences in PKCδ signaling responses. PKCδ exerts membrane-delimited actions in cells activated by agonists that stimulate phosphoinositide hydrolysis. PKCδ is released from membranes as a Tyr313-phosphorylated enzyme that displays a high level of lipid-independent activity and altered substrate specificity during oxidative stress. This study identifies an interaction between PKCδ's Tyr313-phosphorylated hinge region and its phosphotyrosine-binding C2 domain that controls PKCδ's enzymology indirectly by decreasing phosphorylation in the kinase domain ATP-positioning loop at Ser359. We show that wild-type (WT) PKCδ displays a strong preference for substrates with serine as the phosphoacceptor residue at the active site when it harbors phosphomimetic or bulky substitutions at Ser359.In contrast, PKCδ-S359A displays lipid-independent activity toward substrates with either a serine or threonine as the phosphoacceptor residue. Additional studies in cardiomyocytes show that oxidative stress decreases Ser359phosphorylation on native PKCδ and that PKCδ-S359A overexpression increases basal levels of phosphorylation on substrates with both phosphoacceptor site serine and threonine residues. Collectively, these studies identify a C2 domain-pTyr313docking interaction that controls ATP-positioning loop phosphorylation as a novel, dynamically regulated, and physiologically relevant structural determinant of PKCδ catalytic activity.

scholarly journals Protein kinase C mediates platelet secretion and thrombus formation through protein kinase D2

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 416-424 ◽  
Author(s):  
Olga Konopatskaya ◽  
Sharon A. Matthews ◽  
Matthew T. Harper ◽  
Karen Gilio ◽  
Judith M. E. M. Cosemans ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Thrombus Formation ◽  
Dense Granule ◽  
Molecular Pathway ◽  
Kinase C ◽  
Pkc Isoforms ◽  
Dense Granule Secretion ◽  
Granule Secretion

Abstract Platelets are highly specialized blood cells critically involved in hemostasis and thrombosis. Members of the protein kinase C (PKC) family have established roles in regulating platelet function and thrombosis, but the molecular mechanisms are not clearly understood. In particular, the conventional PKC isoform, PKCα, is a major regulator of platelet granule secretion, but the molecular pathway from PKCα to secretion is not defined. Protein kinase D (PKD) is a family of 3 kinases activated by PKC, which may represent a step in the PKC signaling pathway to secretion. In the present study, we show that PKD2 is the sole PKD member regulated downstream of PKC in platelets, and that the conventional, but not novel, PKC isoforms provide the upstream signal. Platelets from a gene knock-in mouse in which 2 key phosphorylation sites in PKD2 have been mutated (Ser707Ala/Ser711Ala) show a significant reduction in agonist-induced dense granule secretion, but not in α-granule secretion. This deficiency in dense granule release was responsible for a reduced platelet aggregation and a marked reduction in thrombus formation. Our results show that in the molecular pathway to secretion, PKD2 is a key component of the PKC-mediated pathway to platelet activation and thrombus formation through its selective regulation of dense granule secretion.

scholarly journals Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C

2003 ◽  
Vol 23 (29) ◽  
pp. 9529-9540 ◽  
Author(s):  
Jian Qiu ◽  
Martha A. Bosch ◽  
Sandra C. Tobias ◽  
David K. Grandy ◽  
Thomas S. Scanlan ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
G Protein ◽  
Hypothalamic Neurons ◽  
Kinase C ◽  
Rapid Signaling ◽  
G Protein Coupled
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