PKA kinases

PPl (8) and its pyrazolopyrimidine analog PP2 (9) [99-108] were first described as potent inhibitors of SFKs with marked selectivity versus ZAP-70, JAK2, EGF-R, and PKA kinases. PPl provided an early key inhibitor of Src kinase to enable determination of its roles in VEGF-mediated angiogenesis and vascular permeability, Src-driven human breast cancer cell lines with respect to both heregulin-dependent or independent growth, and Src-related,... 

Fig. 7.6 Tlie complex of PP2B, PKA, Kinase II, and PKC with AKAP. AKAP targets the kinases and the phosphatase to subsynap-tic sites in neurons. Potential substrates are glutamate- and NMDA (Wmethyl Oalanine) receptors and synaptic Ca2+ channels. (The information on which this scheme is based can be found in Rg. 3 of ref. 14. It is reproduced with permission of the authors and Trends in Biochem. Sci.)...

Naumann and Matter used a set of 26 X-ray structures of eukaryotic protein kinases, which were classified into subfamilies with similar protein-ligand interactions in the ATP binding site. As can be seen in Fig. 3.13, which shows the GPGA score plot, PC 1 separates CDK and MAP/receptor kinases on the left from the family of PKA kinases. The CDK family is represented by two distinct clusters in the target family landscape, formed by two different ATP binding site conformations. They correspond to the activated and inactivated kinase conformations... 

I. Ser/Thr protein kinases A. Cyclic nncleotide-dependent cAMP-dependent (PKA) —R(R/K)X(S /T ) — cAMP... 

B. Ca -calmodnlin (CaM)-dependent Phosphorylase kinase (PhK) —krk qis vrgl— phosphorylation by PKA... 

FIGURE 15.7 Cyclic AMP-dependent protein kinase (also known as PKA) is a 150- to l70-kD R9C9 tetramer in mammalian cells. The two R (regulatory) subunits bind cAMP ( = 3 X 10 M) cAMP binding releases the R subunits from the C (catalytic) subunits. C subunits are enzymatically active as monomers. 

AKAPs are a diverse family of about 75 scaffolding proteins. They are defined by the presence of a structurally conserved protein kinase A (PKA)-binding domain. AKAPs tether PKA and other signalling proteins to cellular compartments and thereby limit and integrate cellular signalling processes at specific sites. This compartmentalization of signalling by AKAPs contributes to the specificity of a cellular response to a given external stimulus (e.g. a particular hormone or neurotransmitter). 

AKAPs are cyclic AMP-dependent protein kinase (PKA)-anchoring proteins, a family of about 30 proteins anchoring PKA at subcellular sites in close vicinity to a certain substrate. 

Heterologous desensitization is a form of desensitization which does not require agonist binding of the receptor. Second messenger dependent kinases such as protein kinase A (PKA) and protein kinase C (PKC) are involved in this form of receptor desensitization. Heterologous desensitization simply depends on the overall kinase activity which is regulated by many different stimuli. 

Protein kinase A (PKA) is a cyclic AMP-dependent protein kinase, a member of a family of protein kinases that are activated by binding of cAMP to their two regulatory subunits, which results in the release of two active catalytic subunits. Targets of PKA include L-type calcium channels (the relevant subunit and site of phosphorylation is still uncertain), phospholam-ban (the regulator of the sarcoplasmic calcium ATPase, SERCA) and key enzymes of glucose and lipid metabolism. 

Sarcoplasmic calcium ATPase this enzyme utilizes the energy gained from hydrolysis of ATP to pump calcium from the cytosol into the stores of the sarcoplasmic reticulum. Its activity is negatively regulated by the closely associated protein phospholamban, and this inhibition is relieved upon phosphorylation of phospholamban by protein kinase A (PKA). 

Single protein kinases such as PKA, PKC, and Ca +-calmodulin (CaM)-kinases, which result in the phosphorylation of serine and threonine residues in target proteins, play a very important role in hormone action. The discovery that the EGF receptor contains an intrinsic tyrosine kinase activity that is activated by the binding of the hgand EGF was an important breakthrough. The insuhn and IGF-I receptors also contain intrinsic... 

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