Protein kinase C also known as PKC is a family of protein kinase enzymes that are involved
in controlling the function of other proteins through the phosphorylation of hydroxyl groups
of serine and threonine amino acid residues on these proteins.
PKC enzymes in turn are activated by signals such as increases in the concentration of
diacylglycerol or calcium ions.
Hence PKC enzymes play important roles in several signal transduction cascades.
The PKC family consists of fifteen isozymes in humans.
They are divided into three subfamilies, based on their second messenger requirements: conventional,
novel, and atypical.
ConventionalPKCs contain the isoforms α, βI, βII, and γ.
These require Ca2+, DAG, and a phospholipid such as phosphatidylserine for activation.
NovelPKCs include the δ, ε, η, and θ isoforms, and require DAG, but do not require Ca2+ for
activation.
Thus, conventional and novel PKCs are activated through the same signal transduction pathway
as phospholipase C. On the other hand, atypicalPKCs require neither Ca2+ nor diacylglycerol for
activation.
The term "protein kinase C" usually refers to the entire family of isoforms.
Isozymes conventional - require DAG, Ca2+, and phospholipid
for activation PKC-α
PKC-β1 PKC-β2
PKC-γ
novel - require DAG but not Ca2+ for activation PKC-δ
PKC-δ1 PKC-δ2
PKC-δ3 PKC-ε
PKC-η PKC-θ
atypical - require neither Ca2+ nor DAG for activation
PKC-ι PKC-ζ
PK-N1 PK-N2
PK-N3
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 esters.
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,lack critical serine, threonine phosphoacceptor residues, keeping the enzyme inactive.
When Ca2+ 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
PKC allows for different functions to be processed; PKB 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.
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 is the upstream kinase responsible for initiating the process by transphosphorylation
of the activation loop.
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 proteins, MAP kinase, transcription factor inhibitor
IκB, the vitamin D3 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 proteins.
The protein kinase C enzymes are known for their long-term activation: They remain activated
after the original activation signal or the Ca2+-wave is gone.
It is presumed that this is achieved by the production of diacylglycerol from phosphatidylinositol
by a phospholipase; fatty acids may also play a role in long-term activation.
Function A multiplicity of functions have been ascribed
to PKC.
Recurring themes are that PKC is involved in receptor desensitization, in modulating
membrane structure events, in regulating transcription, in mediating immune responses, in regulating
cell growth, and in learning and memory.
These functions are achieved by PKC-mediated phosphorylation of other proteins.
However, the substrate proteins present for phosphorylation vary, since protein expression
is different between different kinds of cells.
Thus, effects of PKC are cell-type-specific: Pathology
Protein kinase C, activated by tumor promoter phorbol ester, may phosphorylate potent activators
of transcription, and thus lead to increased expression of oncogenes, promoting cancer
progression, or interfere with other phenomena.
Inhibitors Protein kinase C inhibitors, such as ruboxistaurin,
may potentially be beneficial in peripheral diabetic nephropathy.
The Protein kinase C activator ingenol mebutate, derived from the plant Euphorbia peplus, is
FDA-approved for the treatment of actinic keratosis.
See also Serine/threonine-specific protein kinase
Signal transduction Yasutomi Nishizuka
References
External links protein kinase c at the US National Library
of Medicine Medical Subject Headings