Associated Protein Kinases

Originally, a protein kinase was the first enzyme identified with the CSN purified from human erythrocytes. The CSN-associated kinase activity phosphorylated sev- 

In contrast to c-Jun, phosphorylation of the tumor suppressor p53 by CSN-associated kinases targets the protein for degradation by the Ub system [35]. For p53 stability, modification on Thrl55 is most important as shown by mutational analysis [35] and by using different p53 peptides [31]. Mutation of Thrl55 to Val led to stabilization of the transiently expressed p53 mutant in HeLa as well as in HL60 cells [35]. Inhibitors of CSN-associated kinases such as curcumin [18] caused stabilization of cellular p53 followed by massive cell death [35]. 

In addition to p53 and c-Jun, p27, ICSBP (interferon consensus sequence binding protein) and I/cBa were identified as substrates of the CSN-associated kinases (for a review see Ref [40]). Similar to p53, the phosphorylation of p27 results in 

Identification of associated protein kinases Based on phosphopeptide analyses it became clear that associated kinases modify principally serine and threonine residues. Moreover, the analysis of putative phosphorylation-speciflc consensus sequences of p53, c-Jun, p27, ICSBP and I/cBa revealed that the protein kinase CK2 and a member of the protein kinase C family might be associated with the CSN. 

It has been shown by immunoblotting that CK2 and the protein kinase C/x (also called protein kinase D, PKD) co-purify with the CSN from human erythrocytes [31]. In addition, the two kinases co-immunoprecipitated together with the CSN from HeLa cells. Interaction of CK2 as well as PKD with the CSN is mediated by CSN3, as is the interaction between CK2 and the CSN7 subunit [31]. Interestingly, CSN7 itself is phosphorylated. 

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Uehata M, Ishizaki T, Satoh H et al (1997) Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389 990-994... 

Elledge, S. J., Richman, R., Hall, F. L., Williams, R. T Lodgson, N., and Harper, J. W. (1992). CDK2 encodes a 33-kDa cyclin A-associated protein kinase and is expressed before CDC2 in the cell cycle. Proc. Nad. Acad. Sci. USA 89 2907-2911. 

Ferrel, J. E. Jr., Wo, M., Gerhaart, J. C., and Martin, G. S. (1991). Cell cycle tyrosine phosphorylation of p34c 2 and a microtubule-associated protein kinase homolog in Xenopus oocytes and eggs. Mol. Cell. Biol. 11 1965-1971. 

Morrison, D. K., Kaplan, D. R., Rapp, U., and Roberts, T. M. (1988). Signal transduction from membrane to cytoplasm growth factors and membrane-bound oncogene products increase Raf-1 phosphorylation and associated protein kinase activity. Proc. Natl. Acad. Sci. USA 85 8855-8859. 

Regulation of neurotransmitter receptors the p-adren-ergic receptor. This receptor, of which three subtypes have been cloned, mediates many of the effects of norepinephrine and epinephrine in the brain and peripheral tissues. One of the dramatic features of P-adrenergic receptor function is its rapid desensitization in response to agonist stimulation. It is now known that one important mechanism for this desensitization is phosphorylation of the receptor both by PKA and by a receptor-associated protein kinase, PARK (also called GRK2 Fig. 23-6). 

Alvino CG, Acquaviva AM, Memoli Catanzano AM, Tassi V (1995) Evidence that thyroglobulin has an associated protein kinase activity correlated with the presence of an adenosine triphosphate binding site. Endocrinology 136 3179-3185... 

The DAG produced by the hydrolysis of PIP2 by PLC remains in the plasma membrane where it activates a family of membrane-associated protein kinases collectively termed protein kinase C (PKC). Activated PKC produces a variety of cellular responses, including the regulation of protein synthesis and key metabolic pathways. 

Pigeon, D. Ferrara, P. Gros, E Thibault, J. Rat pheochromocytoma tyrosine hydroxylase is phosphorylated on serine 40 by an associated protein kinase. J. Biol. Chem., 262, 6155-6158 (1987)... 

Dvir, A. Stein, L.Y. Galore, B.L. Dynan, W.S. Purification and characterization of a template-associated protein kinase that phosphorylates RNA polymerase II. J. Biol. Chem., 268, 10440-10447 (1993)... 

Growth hormones, important in diabetes and cancer, activate a receptor with an intrinsic intracellular tyrosine protein kinase activity that passes on the signal by phosphorylating other proteins, often kinases themselves. To date, no specific second messengers have been associated with these systems. The amplification occurs by the turn-on of the receptor-associated protein kinase activity that can phosphorylate many proteins. 

Ray LB, Sturgill TW. Insulin-stimulated microtubule-associated protein kinase is phosphorylated on tyrosine and threonine in vivo. Proc Natl Acad Sci USA. 1988 85 3753-3757. 

Fig. 4. The temporal sequence of events when a resting strip of tracheal smooth muscle is activated by carbacholamine addition at 10 min. There is a transient rise in [Ca2+]c (—) followed by a transient increase in the content (—) of phosphorylated myosin light chains (MLC-P) which lead in turn to the initiation of force development (—). Increased force is sustained even though the content of MLC-P declines. Preceding the sustained phase of force maintenance, there is an increase in the phosphorylation of desmin (D-P), synemin (S-P), caldesmon (CD-P) and a number of low molecular weight cytosolic proteins (X-P). These remain phosphorylated throughout the sustained phase of the response during which there is a sustained increase in Ca2+ cycling across the plasma membrane which regulates the activity of the membrane-associated protein kinase C.

Also known as microtubule associated protein kinases and early response kinases (ERKs). For more synonyms and even more complex descriptions of function, see www.brenda. uni-koeln.de/information/all enzymes.pbp4 ecno 2.7.1.37.MAPK... 

Vilella-Bach, M., Nuzzi, P., Fang, Y, and Chen, J. (1999). The FKBP12-rapamycin-binding domain is required for FKBP12-rapamycin-associated protein kinase activity and G1 progression. J. Biol. Chem. 274,4266-4272. 

Sano, M. and Kitajima, S. (1992) Activation of microtubule-associated protein kinase in PCI 2D cells in response to both fibroblast growth factor and epidermal growth factor and concomitant stimulation of the outgrowth of neurites. J. Neurochem. 58 837-844. 

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