Protein kinase C
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'''[[Protein kinase]] C''' ('PKC', {{EC number|2.7.11.13}}) is a family of protein kinases consisting of ~10 [[isozymes]].<ref name="pmid9601053">{{cite journal | author = Mellor H, Parker PJ | title = The extended protein kinase C superfamily | journal = Biochem. J. | volume = 332 ( Pt 2) | issue = | pages = 281–92 | year = 1998 | pmid = 9601053 | doi = | issn = | url = http://www.biochemj.org/bj/332/bj3320281.htm }}</ref> They are divided into three subfamilies, based on their second messenger requirements: conventional (or classical), novel, and atypical.<ref name="pmid7737456">{{cite journal | author = Nishizuka Y | title = Protein kinase C and lipid signaling for sustained cellular responses | journal = FASEB J. | volume = 9 | issue = 7 | pages = 484–96 | year = 1995 | pmid = 7737456 | doi = | issn = | url = http://www.fasebj.org/cgi/content/abstract/9/7/484 | format = abstract }}</ref> Conventional (c)PKCs contain the [[isoforms]] α, β<sub>I</sub>, β<sub>II</sub>, and γ. These require Ca<sup>2+</sup>, [[diglyceride|diacylglycerol]] (DAG), and a [[phospholipid]] such as [[phosphatidylcholine]] for activation. Novel (n)PKCs include the δ, ε, η, and θ isoforms, and require DAG, but do not require Ca<sup>2+</sup> for activation. Thus, conventional and novel PKCs are activated through the same [[signal transduction]] pathway as [[phospholipase C]]. On the other hand, atypical (a)PKCs (including [[protein kinase Mζ]] and ι / λ isoforms) require neither Ca<sup>2+</sup> nor diacylglycerol for activation. The term "protein kinase C" usually refers to the entire family of isoforms.
==Isozymes==
*conventional - require DAG, Ca<sup>2+</sup>, and phospholipid for activation
** PKC-α ({{Gene|PRKCA}})
** [[PRKCB1|PKC-β<sub>I</sub>]] ({{Gene|PRKCB1}})
** PKC-β<sub>II</sub>
** [[PRKCG|PKC-γ]] ({{Gene|PRKCG}})
* novel - require DAG but not Ca<sup>2+</sup> for activation
** [[PRKCD|PKC-δ]] ({{Gene|PRKCD}})
** [[PRKCE|PKC-ε]] ({{Gene|PRKCE}})
** PKC-η ({{Gene|PRKCH}})
** [[PRKCQ|PKC-θ]] ({{Gene|PRKCQ}})
* atypical - require neither Ca<sup>2+</sup> nor DAG for activation
** [[PRKCI|PKC-ι]] ({{Gene|PRKCI}})
** [[Protein kinase Mζ|PKC-ζ]] ({{Gene|PRKZ}})
** [[PKN1|PK-N1]] ({{Gene|PKN1}})
** PK-N2 ({{Gene|PKN2}})
==Structure==
The structure of all PKCs consists of a regulatory domain and a catalytic domain tethered together by a hinge region. The catalytic region is highly conserved among the different isoforms, as well as, to a lesser degree, among the catalytic region of other [[serine]]/[[threonine]] kinases. The second messenger requirement differences in the isoforms are a result of the regulatory region, which are similar within the classes, but differ among them. Most of the crystal structure of the catalytic region of PKC has not been determined, except for PKC theta and iota. Due to its similarity to other kinases whose crystal structure have been determined, the structure can be strongly predicted.
===Regulatory===
The regulatory domain or the amino-teminus of the PKCs contains several shared subregions. The C1 domain, present in all of the isoforms of PKC has a binding site for DAG as well as non-hydrolysable, non-physiological analogues called [[phorbol ester]]s. This domain is functional and capable of binding DAG in both conventional and novel isoforms, however, the C1 domain in atypical PKCs is incapable of binding to DAG or phorbol esters. The C2 domain acts as a Ca2+ sensor and is present in both conventional and novel isoforms, but functional as a Ca2+ sensor only in the conventional. The pseudosubstrate region, which is present in all three classes of PKC, is a small sequence of amino acids that mimic a substrate and bind the substrate-binding cavity in the catalytic domain keeping the enzyme inactive. When Ca<SUP>2+</SUP> and DAG are present in sufficient concentrations, they bind to the C2 and C1 domain, respectively, and recruit PKC to the membrane. This interaction with the membrane results in release of the pseudosubstrate from the catalytic site and activation of the enzyme. In order for these allosteric interactions to occur, however, PKC must first be properly folded and in the correct conformation permissive for catalytic action. This is contingent upon phosphorylation of the catalytic region, discussed below.
===Catalytic===
The catalytic region or kinase core of the PKA allows for different functions to be processed, PKB (also known as Akt) and PKC kinases contains approximately 40% amino acid sequence similarity. This similarity increases to ~ 70% across PKCs and even higher when comparing within classes. For example, the two atypical PKC isoforms, ζ and ι/λ, are 84% identical (Selbie et al., 1993). Of the over-30 protein kinase structures whose crystal structure has been revealed, all have the same basic organization. They are a bilobal structure with a β sheet comprising the N-terminal lobe and an α helix constituting the C-terminal lobe. Both the ATP- and substrate-binding sites are located in the cleft formed by these two lobes. This is also where the pseudosubstrate domain of the regulatory region binds.
Another feature of the PKC catalytic region that is essential to the viability of the kinase is its phosphorylation. The conventional and novel PKCs have three phosphorylation sites, termed: the activation loop, the turn motif, and the hydrophobic motif. The atypical PKCs are phosphorylated only on the activation loop and the turn motif. Phosphorylation of the hydrophobic motif is rendered unnecessary by the presence of a glutamic acid in place of a serine, which, as a negative charge, acts similar in manner to a phosphorylated residue. These phosphorylation events are essential for the activity of the enzyme, and 3-phosphoinositide-dependent protein kinase-1 ([[PDK1]]) is the upstream kinase responsible for initiating the process by transphosphorylation of the activation loop.(Balendran et al., 2000)
The consensus sequence of protein kinase C enzymes is similar to that of [[protein kinase A]], since it contains basic amino acids close to the Ser/Thr to be phosphorylated. Their substrates are, e.g., [[MARCKS protein]]s, [[MAP kinase]], transcription factor inhibitor IκB, the [[vitamin D]]<sub>3</sub> receptor [[VDR]], [[Raf kinase]], [[calpain]], and the [[epidermal growth factor receptor]].
==Activation==
Upon activation, protein kinase C enzymes are translocated to the [[plasma membrane]] by [[RACK protein]]s (membrane-bound receptor for activated protein kinase C proteins). The protein kinase C enzymes are known for their long-term activation: They remain activated after the original activation signal or the Ca<sup>2+</sup>-wave is gone. This is presumably achieved by the production of diacylglycerol from phosphatidylcholine by a [[phospholipase]]; fatty acids may also play a role in long-term activation.
==Function== <!--Function of Protein kinase C redirects here-->
PKC phosphorylates other [[proteins]], altering their function. However, what proteins are available for phosphorylation depends on in what kind of cell the PKC activity is present, since protein composition varies from cell type to cell type. Thus, effects of PKC are cell-type specific:
===Overview table===
{| class="wikitable sortable"
|-
! Cell type
! Organ/system
! Activators <BR> [[ligands]] --> [[Gq alpha subunit|G<sub>q</sub>]]-[[G-protein coupled receptor|GPCR]]s
! Effects
|-
| [[smooth muscle]] cell ([[gastrointestinal tract]] [[sphincter]]s) || [[Digestive system]] ||
*[[prostaglandin F2α]]<ref name="Biancani"/> -->
*[[thromboxane]]s<ref name="Biancani">[http://www.nature.com/gimo/contents/pt1/full/gimo24.html Signal transduction in lower esophageal sphincter circular muscle] Piero Biancani, Ph.D. and Karen M. Harnett, Ph.D.</ref> --> [[Thromboxane receptor]]
|| contraction
|-
| [[smooth muscle]] cell ([[iris dilator muscle]]) || [[Sensory system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
|| contraction
|-
| [[smooth muscle]] cell ([[iris constrictor muscle]]) || [[Sensory system]] ||
*[[acetylcholine]] --> [[M3 receptor]]
|| contraction
|-
| [[smooth muscle]] cell ([[ciliary muscle]]) || [[Sensory system]] ||
*[[acetylcholine]] --> [[M3 receptor]]
|| contraction
|-
| [[smooth muscle]] cell ([[urethral sphincter]]) || [[Urinary system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
|| contraction
|-
| [[smooth muscle]] cell ([[uterus]]) || [[Reproductive system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
|| contraction
|-
| [[smooth muscle]] cell ([[arrector pili muscles]]) || [[Integumentary system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
|| contraction
|-
| [[smooth muscle]] cell ([[ureter]]) || [[Urinary system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
|| contraction
|-
| [[smooth muscle]] cell ([[urinary bladder]]) || [[Urinary system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
||
*contraction<ref name="purves">{{cite book | author = Fitzpatrick, David; Purves, Dale; Augustine, George | title = Neuroscience | publisher = Sinauer | location = Sunderland, Mass | year = 2004 | | edition = Third Edition | chapter = Table 20:2 | pages = | isbn = 0-87893-725-0 | oclc = | doi = }}</ref><ref name="pmid14634460">{{cite journal | author = Chou EC, Capello SA, Levin RM, Longhurst PA | title = Excitatory α<sub>1</sub>-adrenergic receptors predominate over inhibitory β-receptors in rabbit dorsal detrusor | journal = J. Urol. | volume = 170 | issue = 6 Pt 1 | pages = 2503–7 | year = 2003 | pmid = 14634460 | doi = 10.1097/01.ju.0000094184.97133.69 }}</ref>
|-
| [[smooth muscle]] cell (vascular) || [[Circulatory system]] ||
*[[5-HT]] --> [[5-HT2A receptor]]
*[[Adrenergic agonist]]s --> [[α1 receptor]]
|
*[[Vasoconstriction]]<ref name=Rang187/><ref name=Rang127> {{cite book |author=Rang, H. P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=0-443-07145-4 |oclc= |doi=}} Page 127 </ref>
|-
| [[smooth muscle]] cell ([[seminal tract]]<ref name=Rang163> {{cite book |author=Rang, H. P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=0-443-07145-4 |oclc= |doi=}} Page 163 </ref>) || [[Reproductive system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
|| [[ejaculation]]
|-
| [[smooth muscle]] cell ([[gastrointestinal tract|GI tract]]) || [[Digestive system]] ||
*[[5-HT]] --> [[5-HT2A receptor|5-HT2A]] or [[5-HT2B receptor]]<ref name=Rang187/>
*[[acetylcholine]] (ACh) --> [[M3 receptor]]
||
*contraction <ref>[http://ajpgi.physiology.org/cgi/content/full/275/1/G1 G Protein-Coupled Receptors in Gastrointestinal Physiology IV. Neural regulation of gastrointestinal smooth muscle] Kenton M. Sanders</ref>
|-
| [[smooth muscle]] cell ([[bronchi]]) || [[Respiratory system]] ||
*[[5-HT]] --> [[5-HT2A receptor]]
*[[Adrenergic agonist]]s --> [[α1 receptor]]
*[[acetylcholine]] --> [[M3 receptor|M3]]<ref name="isbn0-07-142280-3">{{cite book | author = Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred | title = Goodman & Gilman's the pharmacological basis of therapeutics | publisher = McGraw-Hill | location = New York | edition = 11<sup>th</sup> Ed. | year = 2006 | pages = page 185 | isbn = 0-07-142280-3 | oclc = | doi = }}</ref> and [[M1 receptor]] <ref name="entrezM1"/>
|| [[bronchoconstriction]] <ref name=Rang187/>
|-
| [[proximal convoluted tubule cell]] || [[kidney]] ||
*[[angiotensin II]] --> [[AT1 receptor]]
*[[Adrenergic agonist]]s --> [[α1 receptor]]
||
*Stimulate [[NHE3]] --> H<sup>+</sup> secretion & Na<sup>+</sup> reabsorption<ref name=boron787> {{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |location= |year= |pages= |isbn=1-4160-2328-3 |oclc= |doi=}} Page 787 </ref>
*Stimulate basolateral [[Na-K ATPase]] --> Na<sup>+</sup> reabsorption<ref name=boron787/>
|-
| [[neurons]] in [[autonomic ganglia]] || [[nervous system]] || [[acetylcholine]] --> [[M1 receptor]] || [[excitatory postsynaptic potential|EPSP]]
|-
| [[neurons]] in [[central nervous system|CNS]] || [[nervous system]] ||
*[[5-HT]] --> [[5-HT2A receptor]]
*[[acetylcholine]] --> [[M1 receptor]]
||
*neuronal excitation (5-HT) <ref name=Rang187> {{cite book |author=Rang, H. P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=0-443-07145-4 |oclc= |doi=}} Page 187 </ref>
*memory? (acetylcholine) <ref name=Rang>{{cite book | first = | last =Rang HP, Dale MM, Ritter JM, Moore PK| authorlink = | coauthors = | year = 2003| month = | title = Pharmacology | chapter = Ch. 10 | editor = | others = | edition = 5<sup>th</sup> edition | pages = page 139 | publisher = Elsevier Churchill Livingstone| location = | id = ISBN 0-443-07145-4| url = }}</ref>
|-
| [[platelet]]s || [[Circulatory system]] || [[5-HT]] --> [[5-HT2A receptor]]<ref name=Rang187/> || Aggregation<ref name=Rang187/>
|-
| [[ependymal cell]]s ([[choroid plexus]]) || [[Ventricular system]] || [[5-HT]] --> [[5-HT2C receptor]]<ref name=Rang187/> || ↑[[cerebrospinal fluid]] secretion<ref name=Rang187/>
|-
| [[heart muscle]] || [[circulatory system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
|| Positive [[ionotropic effect]]<ref name="purves">{{cite book | author = Fitzpatrick, David; Purves, Dale; Augustine, George | title = Neuroscience | publisher = Sinauer | location = Sunderland, Mass | year = 2004 | | edition = Third Edition | chapter = Table 20:2 | pages = | isbn = 0-87893-725-0 | oclc = | doi = }}</ref>
|-
| [[Serous cell]]s ([[salivary gland]]) || [[Digestive system]] ||
*[[acetylcholine]] --> [[M1 receptor|M1]] and [[M3 receptor]]s
*[[Adrenergic agonist]]s --> [[α1 receptor]]
||
*↑Secretion<ref name=purves/>
*Increase salivary [[potassium]] levels.
|-
| [[Serous cell]]s ([[lacrimal gland]]) || [[Digestive system]] ||
*[[acetylcholine]] --> [[M3 receptor]]
||
*↑Secretion<ref name=Rang127/>
|-
| [[adipocyte]] || [[Digestive system]]/[[Endocrine system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
||
*[[Glycogenolysis]] and [[gluconeogenesis]]<ref name=purves/>
|-
| [[hepatocyte]] || [[Digestive system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
||
*[[Glycogenolysis]] and [[gluconeogenesis]]<ref name=purves/>
|-
| [[sweat gland]] cells || [[Integumentary system]] ||
*[[Adrenergic agonist]]s --> [[α1 receptor]]
||
*↑Secretion<ref name=purves/>
|-
| [[parietal cell]]s || [[Digestive system]] || [[acetylcholine]] --> [[M1 receptor]]s<ref name="entrezM1">{{cite web | title = Entrez Gene: CHRM1 cholinergic receptor, muscarinic 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1128| accessdate = }}</ref> || ↑ [[gastric acid]] secretion
|}
==See also==
* [[Serine/threonine-specific protein kinase]]
* [[Signal transduction]]
== References ==
{{Reflist|2}}
==External links==
* {{MeshName|protein+kinase+c}}
{{Serine/threonine-specific protein kinases}}
[[Category:EC 2.7]]
[[Category:Protein kinases]]
[[de:Proteinkinase C]]
[[he:פרוטאין קינאז C]]