Protein serine/threonine kinases (E.C. 2.7.11.-) use the co-substrate ATP to phosphorylate serine and/or threonine residues on target proteins. Analysis of the human genome suggests the presence of 518 protein kinases in man, with over 100 protein kinase-like pseudogenes [34]. It is beyond the scope of the Guide to list all these protein kinase activities; this summary focuses on AGC protein kinases associated with GPCR signalling, which may be divided into 15 subfamilies in man.

Most inhibitors of these enzymes have been assessed in cell-free investigations and so may appear to ‘lose’ potency and selectivity in intact cell assays. In particular, ambient ATP concentrations may be influential in responses to inhibitors, since the majority are directed at the ATP binding site [11] .

G protein-coupled receptor kinases, epitomized by βARK, are involved in the rapid phosphorylation and desensitization of GPCR. Classically, high concentrations of β₂-adrenoceptor agonists binding to the receptor lead to the consequent activation and dissociation of the heterotrimeric G protein G_s. Gα_s activates adenylyl cyclase activity, while Gβγ subunits perform other functions, one of which is to recruit βARK to phosphorylate serine/threonine residues in the cytoplasmic tail of the β₂-adrenoceptor. The phosphorylated receptor binds, with high affinity, a member of the arrestin family (ENSFM00250000000572), which prevents further signalling through the G protein (uncoupling) and may allow interaction with scaffolding proteins, such as clathrin, with the possible consequence of internalization and/or degradation.

Loss-of-function mutations in RHOK or retinal and pineal gland arrestin (ENSG00000130561) are associated with Oguchi disease, a form of congenital stationary night blindness.

Cyclic AMP-mediated signalling involves regulation of cyclic nucleotide-gated ion channels, members of the Rap guanine nucleotide exchange family (Epac, ENSFM00250000000899) and activation of protein kinase A (PKA, also known as cyclic AMP-dependent protein kinase). PKA is a heterotetrameric enzyme composed of two regulatory and two catalytic subunits, which can be distinguished from Epac (exchange protein directly activated by cAMP, [12]) by differential activation by N⁶ benzyl-cAMP (see Table) and 8-pCPT-2'-O-Me-cAMP, respectively [29].

Other members of the PKA family are PRKX (X-linked protein kinase, PKX1, ENSG00000183943) and PRKY (Y-linked protein kinase, ENSG00000099725). PRKX and PRKY are expressed on X and Y chromosomes, respectively, and appear to interchange in some XX males and XY females [39].

The action of phosphatidylinositol 3-kinase (PI3K), a downstream kinase activated by receptor tyrosine kinases, produces a series of phosphorylated phosphoinositides, which recruit 3-phosphoinositide-dependent kinase (PDK1) activity to the plasma membrane, leading to activation of PKB (also known as Akt, Rac serine/threonine protein kinase, v-akt murine thymoma viral oncogene). PKB may be activated by PIP₃, PDK1-mediated phosphorylation [2] and mTORC2-mediated phosphorylation [23,38].

Protein kinase C is the target for the tumour-promoting phorbol esters, such as tetradecanoyl-β-phorbol acetate (TPA, also known as phorbol 12-myristate 13-acetate).

Classical protein kinase C isoforms: PKCα, PKCβ, PKCγ. Members of the classical protein kinase C family are activated by Ca²⁺ and diacylglycerol, and may be inhibited by GF109203X, calphostin C, Gö6983, chelerythrine and Ro318220.

Novel protein kinase C isoforms: PKCδ, PKCε, PKCη, PKCθ and PKCμ. Members of the classical protein kinase C family are activated by diacylglycerol and may be inhibited by calphostin C, Gö6983 and chelerythrine.

Atypical protein kinase C isoforms:PKCι, PKCζ.

Cyclic GMP-dependent protein kinase is a dimeric enzyme activated by cGMP generated by particulate guanylyl cyclases or soluble guanylyl cyclases.

MAP kinases (CMGC kinases, ENSF00000000137) may be divided into three major families: ERK, JNK and p38 MAP kinases.

ERK may be activated by phosphorylation by the dual specificity mitogen-activated kinase kinases, MAP2K1 (also known as MEK1, ENSG00000169032) and MAP2K2 (also known as MEK2, ENSG00000126934). The inhibitors PD98059 [1,14] and U0126 [15,17] act to inhibit these enzymes [11], and are used to inhibit ERK1 and ERK2.

JNK may be activated by phosphorylation by the dual specificity mitogen-activated kinase kinases, MAP2K4 (also known as JNKK1, ENSG00000065559) and MAP2K7 (also known as JNKK2, ENSG00000076984).

p38 may be activated by phosphorylation by the dual specificity mitogen-activated kinase kinases, MAP2K3 (also known as MEK3, ENSG00000034152) and MAP2K6 (also known as SAPKK3, ENSG00000108984).

SB203580 has been reported to inhibit p38α and p38β with pIC₅₀ values of 8.0 and 7.0, respectively [16]. SB202190 inhibits p38β [33].

Rho kinase (also known as P160ROCK, Rho-activated kinase) is activated by members of the Rho small G protein family (ENSFM00500000269651), which are activated by GTP exchange factors, such as ARHGEF1 (p115-RhoGEF, ENSG00000076928), which in turn may be activated by Gα_12/13 subunits [31].

Rho kinase may be inhibited selectively by Y27632 [43] or fasudil [3].

For many of these remaining protein kinases, there is less information about the regulation and substrate specificity, as well as a paucity of pharmacological data

AMP-activated protein kinase is a heterotrimeric protein kinase, made up of α, β and γ subunits, while casein kinase 2 is a heterotetrameric protein kinase, made up of 2 β subunits with two other subunits of α and/or α’ composition. STO609 is an inhibitor of calmodulin kinase kinase (ENSFM00250000001201, [42]), an upstream activator of calmodulin-dependent kinase.

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