Regulation of Protein Kinase

In addition to regulation by cAMP, protein kinase A is also subject to other regulatory influences. Thus, the C subunit may be specifically phosphorylated (see 7.2.1). It is not clear, however, which protein kinase is responsible for phosphorylation of the C suhunit. 

Regulation of protein kinase A may also take place via its subceUular localization. Protein kinase A containing the RII subunit is foimd associated with the cytoskeleton and with the Golgi apparatus. Anchoring of protein kinase A to the subceUular compartments is mediated by specific proteins known as protein kinase A anchor proteins (AKAP A kinase mchor protein). The RII subimit functions as a specific locaUzation subunit by mediating the interaction of protein kinase A with the anchor proteins. 

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Oishi, K., Raynot, RL., Charp, P.A. and Kuo, J.F. (1988). Regulation of protein kinase C by lysophospholipids. Potential role in signal transduction. J. Biol. Chem. 263, 6865-6871. 

Harnett, W. and Harnett, M.M. (1993) Inhibition of murine B cell proliferation and down-regulation of protein kinase C levels by a phosphorylcholine-containing filarial excretory-secretory product. Journal of Immunology 151, 4829-4837. 

Woloschak, G.E., C.M. Chang-Liu, and P. Shearin-Jones. 1990a. Regulation of protein kinase C by ionizing radiation. Cancer Res. 50 3963-3967. 

Blobe GC, Obeid LM, Hannun YA (1994) Regulation of protein kinase C and role in cancer biology. Cancer Metastasis Rev 13 411-431... 

Regulation of protein kinase A by cAMP takes place by the following mechanism. An increase in cAMP concentration, triggered by activation of adenylyl cyclase, leads to binding of cAMP at specific binding sites on the regulatory subunit. The R subunits dissociate from the tetramer, the catalytic subunits are released from inhibition by the regulatory subunits and can thus phosphorylate substrate proteins. 

Fig. 6.2. Regulation of protein kinase A via cAMP. Protein kinase A is a tetrameric enyzme composed of two catalytic subunits (C) and two regulatory subunits (R). In the R2C2 form, protein kinase A is inactive. Binding of cAMP to R leads to dissociation of the tetrameric enyzme into the R2 form with bound cAMP and free C subunits. In the free form, C is active and catalyzes the phosphorylation of substrate proteins (S) at Ser/Thr residues.

The best characterized substrate of Ca Vcalmodulin is the Ca /calmodulin-depen-dent protein kinase (CaM kinase). CaM kinase has an important function in neuronal signal transduction. The mechanism of Ca Vcalmodulin activation of CaM kinase is described in more detail in Section 7.4, together with regulation of protein kinases. Another substrate of Ca Vcalmodulin is myosin light chain kinase (MLCK), involved in contraction of smooth musculature. 

Fimctions and regulation of protein kinase C are shown schematically in Fig. 7.10. 

Fig. 7.10. Functions and regulation of protein kinase C. Receptor-controlled signal pathways lead to formation of the intracellular messenger substances and diacylglycerol (DAG), that, like phorbol ester (TPA), activate protein kinase C (PKC). Translocation to the cell membrane is linked with activation of protein kinase C receptors for protein kinase C, the RACK proteins, are also involved. Substrates of protein kinase C are the MARCKS proteins and other proteins associated with the cytoskeleton. Other substrates are the Raf kinase (see Chapter 10) and the receptor for vitamin D3 (VDR, see Chapter 4).

Newton, A.C. Regulation of protein kinase C (1997) Curr. Op. Cell Biol. 9,161-167... 

Gopalakrishna, R., Chen, Z.H. Gundimeda, U. (1994) Tobacco smoke tumor promoters, catechol and hydroquinone, induce oxidative regulation of protein kinase C and influence invasion and metastasis of lung carcinoma cells. Proc. natl Acad. Sci. USA, 91, 12233-12237... 

Guglielmetti F., Rattray M., Baldessari S., Butelli E., Samanin R., and Bendotti C. (1997). Selective up-regulation of protein kinase C epsilon in granule cells after kainic acid-induced seizures in rat. Brain Res. Mol. Brain Res. 49 188-196. 

Nolen, B., Taylor, S., Ghosh, G. Regulation of protein kinases controlling activity through activation segment conformation. Mol. Cell 2004, 15, 661-675. 

Figure 10.28. Regulation of Protein Kinase A. The binding of four molecules of cAMP activates protein kinase A by dissociating the inhibited holoenzyme (R2C2) into a regulatory subunit (R2) and two catalytically active subunits (C).

Resjo, and I. Castan, et ah. Regulation of protein kinase B in rat adipocytes by insulin, vanadate, and peroxovanadate. Membrane translocation in response to peroxovanadate, J. Biol. Chem., 1997, 272, 21520-21526. 

Mosior M, Golini ES, Epand RM. Chemical specificity and physical properties of the lipid bilayer in the regulation of protein kinase C by anionic phospholipids evidence for the lack of a specific binding site for phosphatidylserine. Proc Natl Acad Sci USA 1996 93 1907-1912. 

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