Protein kinase Cδ and apoptosis

2007 ◽  
Vol 35 (5) ◽  
pp. 1001-1004 ◽  
Author(s):  
M.E. Reyland
Keyword(s):  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Nuclear Accumulation ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Caspase Cleavage ◽  
Kinase C ◽  
Pkc Protein Kinase C ◽  
Apoptotic Activity

The PKC (protein kinase C) family regulates diverse cellular functions and specific isoforms have been shown to be critical regulators of cell proliferation and survival. In particular, PKCδ is known to be a critical pro-apoptotic signal in many cell types. Work in our laboratory has focused on understanding the molecular mechanisms through which PKCδ regulates apoptosis and on how the pro-apoptotic activity of this ubiquitous kinase is regulated such that cells only activate the apoptotic cascade when appropriate. We have identified multiple regulatory steps that activate the pro-apoptotic function of PKCδ in response to genotoxins. Our studies show that apoptotic signals induce rapid post-translational modification of PKCδ in the regulatory domain, which facilitates translocation of the kinase from the cytoplasm to the nucleus. Active caspase 3 also accumulates in the nucleus under these conditions, resulting in caspase cleavage of PKCδ and generation of a constitutively activated form of PKCδ [δCF (PKCδ catalytic fragment)]. In contrast with PKCδ, δCF is constitutively present in the nucleus, and this nuclear accumulation of PKCδ is essential for apoptosis. Thus our studies suggest that tight regulation of nuclear import and of PKCδ is critical for cell survival and that caspase cleavage of PKCδ in the nucleus signals an irreversible commitment to apoptosis.

Protein kinase C-α and the regulation of diverse cell responses

2017 ◽  
Vol 8 (3-4) ◽  
pp. 143-153 ◽  
Author(s):  
Rishi Kant Singh ◽  
Sanjay Kumar ◽  
Pramod Kumar Gautam ◽  
Munendra Singh Tomar ◽  
Praveen Kumar Verma ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cellular Localization ◽  
Cellular Transformation ◽  
Cell Types ◽  
Adapter Proteins ◽  
Cellular Functions ◽  
Cell Responses ◽  
Kinase C ◽  
Cellular Compartments

AbstractProtein kinase C (PKC) comprises a family of lipid-sensitive enzymes that have been involved in a broad range of cellular functions. PKC-α is a member of classical PKC with ubiquitous expression and different cellular localization. This unique PKC isoform is activated by various signals which evoke lipid hydrolysis, after activation it interacts with various adapter proteins and is localized to specific cellular compartments where it is devised to work. The universal expression and activation by various stimuli make it a perfect player in uncountable cellular functions including differentiation, proliferation, apoptosis, cellular transformation, motility, adhesion and so on. However, these functions are not intrinsic properties of PKC-α, but depend on cell types and conditions. The activities of PKC-α are managed by the various pharmacological activators/inhibitors and antisense oligonucleotides. The aim of this review is to elaborate the structural feature, and provide an insight into the mechanism of PKC-α activation and regulation of its key biological functions in different cellular compartments to develop an effective pharmacological approach to regulate the PKC-α signal array.

Regulation of exocytosis by protein kinase C

2005 ◽  
Vol 33 (6) ◽  
pp. 1341-1344 ◽  
Author(s):  
A. Morgan ◽  
R.D. Burgoyne ◽  
J.W. Barclay ◽  
T.J. Craig ◽  
G.R. Prescott ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Types ◽  
Neuroendocrine Cells ◽  
Protein Targets ◽  
Site Specific ◽  
Regulated Exocytosis ◽  
Kinase C ◽  
Pkc Protein Kinase C

PKC (protein kinase C) has been known for many years to modulate regulated exocytosis in a wide variety of cell types. In neurons and neuroendocrine cells, PKC regulates several different stages of the exocytotic process, suggesting that these multiple actions of PKC are mediated by phosphorylation of distinct protein targets. In recent years, a variety of exocytotic proteins have been identified as PKC substrates, the best characterized of which are SNAP-25 (25 kDa synaptosome-associated protein) and Munc18. In the present study, we review recent evidence suggesting that site-specific phosphorylation of SNAP-25 and Munc18 by PKC regulates distinct stages of exocytosis.

scholarly journals Atypical protein kinase C induces cell transformation by disrupting Hippo/Yap signaling

2015 ◽  
Vol 26 (20) ◽  
pp. 3578-3595 ◽  
Author(s):  
Andrew Archibald ◽  
Maia Al-Masri ◽  
Alyson Liew-Spilger ◽  
Luke McCaffrey
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Epithelial Cells ◽  
3D Culture ◽  
Cell Junctions ◽  
Nuclear Accumulation ◽  
Cell Phenotype ◽  
Atypical Protein Kinase C ◽  
Atypical Protein Kinase ◽  
Kinase C

Epithelial cells are major sites of malignant transformation. Atypical protein kinase C (aPKC) isoforms are overexpressed and activated in many cancer types. Using normal, highly polarized epithelial cells (MDCK and NMuMG), we report that aPKC gain of function overcomes contact inhibited growth and is sufficient for a transformed epithelial phenotype. In 2D cultures, aPKC induced cells to grow as stratified epithelia, whereas cells grew as solid spheres of nonpolarized cells in 3D culture. aPKC associated with Mst1/2, which uncoupled Mst1/2 from Lats1/2 and promoted nuclear accumulation of Yap1. Of importance, Yap1 was necessary for aPKC-mediated overgrowth but did not restore cell polarity defects, indicating that the two are separable events. In MDCK cells, Yap1 was sequestered to cell–cell junctions by Amot, and aPKC overexpression resulted in loss of Amot expression and a spindle-like cell phenotype. Reexpression of Amot was sufficient to restore an epithelial cobblestone appearance, Yap1 localization, and growth control. In contrast, the effect of aPKC on Hippo/Yap signaling and overgrowth in NMuMG cells was independent of Amot. Finally, increased expression of aPKC in human cancers strongly correlated with increased nuclear accumulation of Yap1, indicating that the effect of aPKC on transformed growth by deregulating Hippo/Yap1 signaling may be clinically relevant.

scholarly journals Respiratory-induced coenzyme Q biosynthesis is regulated by a phosphorylation cycle of Cat5p/Coq7p

2011 ◽  
Vol 440 (1) ◽  
pp. 107-114 ◽  
Author(s):  
Alejandro Martín-Montalvo ◽  
Isabel González-Mariscal ◽  
Sergio Padilla ◽  
Manuel Ballesteros ◽  
David L. Brautigan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Kinase ◽  
Regulatory Mechanism ◽  
Coenzyme Q ◽  
In Vitro Assays ◽  
Respiratory Metabolism ◽  
Total Absence ◽  
Kinase C ◽  
Pkc Protein Kinase C

CoQ6 (coenzyme Q6) biosynthesis in yeast is a well-regulated process that requires the final conversion of the late intermediate DMQ6 (demethoxy-CoQ6) into CoQ6 in order to support respiratory metabolism in yeast. The gene CAT5/COQ7 encodes the Cat5/Coq7 protein that catalyses the hydroxylation step of DMQ6 conversion into CoQ6. In the present study, we demonstrated that yeast Coq7 recombinant protein purified in bacteria can be phosphorylated in vitro using commercial PKA (protein kinase A) or PKC (protein kinase C) at the predicted amino acids Ser20, Ser28 and Thr32. The total absence of phosphorylation in a Coq7p version containing alanine instead of these phospho-amino acids, the high extent of phosphorylation produced and the saturated conditions maintained in the phosphorylation assay indicate that probably no other putative amino acids are phosphorylated in Coq7p. Results from in vitro assays have been corroborated using phosphorylation assays performed in purified mitochondria without external or commercial kinases. Coq7p remains phosphorylated in fermentative conditions and becomes dephosphorylated when respiratory metabolism is induced. The substitution of phosphorylated residues to alanine dramatically increases CoQ6 levels (256%). Conversely, substitution with negatively charged residues decreases CoQ6 content (57%). These modifications produced in Coq7p also alter the ratio between DMQ6 and CoQ6 itself, indicating that the Coq7p phosphorylation state is a regulatory mechanism for CoQ6 synthesis.

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 C-terminal tail polyglycylation and polyglutamylation alter microtubule mechanical properties

2019 ◽  
Author(s):  
Kathryn P. Wall ◽  
Harold Hart ◽  
Thomas Lee ◽  
Cynthia Page ◽  
Taviare L. Hawkins ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Molecular Mechanisms ◽  
High Stress ◽  
Resonance Spectroscopy ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Peptide Backbone ◽  
Post Translational Modifications ◽  
Intrinsic Stiffness ◽  
Insight Into

ABSTRACTMicrotubules are biopolymers that perform diverse cellular functions. The regulation of microtubule behavior occurs in part through post-translational modification of both the α- and β- subunits of tubulin. One class of modifications is the heterogeneous addition of glycine and glutamate residues to the disordered C-terminal tails of tubulin. Due to their prevalence in stable, high stress cellular structures such as cilia, we sought to determine if these modifications alter the intrinsic stiffness of microtubules. Here we describe the purification and characterization of differentially-modified pools of tubulin from Tetrahymena thermophila. We found that glycylation on the α-C-terminal tail is a key determinant of microtubule stiffness, but does not affect the number of protofilaments incorporated into microtubules. We measured the dynamics of the tail peptide backbone using nuclear magnetic resonance spectroscopy. We found that the spin-spin relaxation rate (R2) showed a pronounced decreased as a function of distance from the tubulin surface for the α-tubulin tail, indicating that the α-tubulin tail interacts with the dimer surface. This suggests that the interactions of the α-C-terminal tail with the tubulin body contributes to the stiffness of the assembled microtubule, providing insight into the mechanism by which glycylation and glutamylation can alter microtubule mechanical properties.SIGNIFICANCEMicrotubules are regulated in part by post-translational modifications including the heterogeneous addition of glycine and glutamate residues to the C-terminal tails. By producing and characterizing differentially-modified tubulin, this work provides insight into the molecular mechanisms of how these modifications alter intrinsic microtubule properties such as flexibility. These results have broader implications for mechanisms of how ciliary structures are able to function under high stress.

Mitogen stimulation of Na+-H+ exchange: differential involvement of protein kinase C

1987 ◽  
Vol 253 (2) ◽  
pp. C219-C229 ◽  
Author(s):  
L. L. Muldoon ◽  
G. A. Jamieson ◽  
A. C. Kao ◽  
H. C. Palfrey ◽  
M. L. Villereal
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Types ◽  
Intact Cells ◽  
Kinase C ◽  
Protein Kinase C Activity ◽  
Human Fibroblast Strains ◽  
Stimulation Of

The mitogen-induced activation of Na+-H+ exchange was investigated in two cultured human fibroblast strains (HSWP and WI-38 cells) that, based on previous studies, differed in their response to the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) (L. M. Vincentini and M. L. Villereal, Proc. Natl. Acad. Sci. USA 82: 8053-8056, 1985). The role of protein kinase C in the activation of Na+-H+ exchange was investigated by comparing the effects of TPA on Na+ influx, in vitro phosphorylation, and in vivo phosphorylation in both cell types. Although both cell types have significant quantities of protein kinase C activity that can be activated by TPA in intact cells, the addition of TPA to intact cells stimulates Na+ influx in WI-38 cells but not in HSWP cells, indicating that in HSWP cells the stimulation of protein kinase C is not sufficient to activate the Na+-H+ exchanger. Cells were then depleted of protein kinase C activity by chronic treatment with high doses of TPA. Both HSWP and WI-38 cells were rendered protein kinase C deficient by this treatment as determined by in vitro and in vivo phosphorylation studies. Protein kinase C-deficient HSWP cells lose the ability for TPA to inhibit the serum-induced activation of Na+-H+ exchange, but there is no reduction in the stimulation of Na+ influx by serum, bradykinin, vasopressin, melittin, or vanadate, indicating that protein kinase C activity is not necessary for the mitogen-induced activation of Na+-H+ exchange in HSWP cells by agents known to stimulate phosphatidylinositol turnover (G. A. Jamieson and M. Villereal. Arch. Biochem. Biophys. 252: 478-486, 1987). In contrast, depletion of protein kinase C activity in WI-38 cells significantly reduces both the TPA- and the serum-induced activation of the Na+-H+ exchange system, suggesting that protein kinase C activity is necessary for at least a portion of the mitogen-induced activation of the Na+-H+ exchanger in WI-38 cells. These results indicate that the mechanisms for regulating Na+-H+ exchange can differ dramatically between different types of fibroblasts.

scholarly journals Effect of secretagogues on chromogranin A synthesis in bovine cultured chromaffin cells. Possible regulation by protein kinase C

1989 ◽  
Vol 260 (3) ◽  
pp. 915-922 ◽  
Author(s):  
J P Simon ◽  
M F Bader ◽  
D Aunis
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Chromogranin A ◽  
Chromaffin Cells ◽  
Cell Types ◽  
Term Treatment ◽  
Synthesis Rate ◽  
Kinase C ◽  
Long Term Treatment ◽  
Bovine Chromaffin Cells

Chromogranin A is a major component of storage granules in many different secretory cell types. After [35S]methionine labelling of proteins from cultured bovine chromaffin cells, chromogranin A was immunoprecipitated with specific antibodies, and the radioactivity incorporated into chromogranin A was determined and used as an index of its synthesis rate. Depolarization of cells with nicotine or high K+ evoked a Ca2+-dependent increase in chromogranin A synthesis, whereas muscarine, which does not evoke significant Ca2+ influx from bovine chromaffin cells, had no effect on chromogranin A synthesis. Forskolin, an activator of adenylate cyclase, affected neither the basal nor the nicotine-stimulated rate of chromogranin A synthesis. In contrast, 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of protein kinase C, significantly enhanced the incorporation of radioactivity into chromogranin A. Sphingosine, an inhibitor of protein kinase C, abolished both nicotine-stimulated and TPA-induced chromogranin A synthesis. In addition, long-term treatment of chromaffin cells with TPA decreased protein kinase C activity and inhibited the nicotine-stimulated chromogranin A synthesis. These results suggest that protein kinase C may play an important role in the control of chromogranin A synthesis.

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