Proteins Serine

The a subunits, for which two isoforms exist in mammals (al, a2), contain conventional protein serine/threonine kinase domains at the N-terminus, with a threonine residue in the activation loop (Thr-172) that must be phosphorylated by upstream kinases (see below) before the kinase is active. The kinase domain is followed by an autoinhibitory domain, whose effect is somehow relieved by interaction with the other subunits. The C-terminal domain of the a subunit is required for the formation of a complex with the C-terminal domain of the (3 subunit, which in turn mediates binding to the y subunit. The al and a2 catalytic subunit isoforms are widely distributed, although a2 is most abundant in muscle and may be absent in cells of the endothelial/hemopoietic lineage. 

Cohen PTW (1997) Novel protein serine/threonine phosphatases variety ist he spice of life. Trends Biochem Sci 22 245-251... 

Homologies pir7 protein Serine Havoproteins Alcohol ... 

Cytoplasmic serine/threonine protein kinases catalyze the transfer of phosphate groups to serine and threonine residues of target proteins. Serine/threonine kinases have been recognized as the products of protooncogenes (e.g., c-mos, c-raj) or as kinases intimately involved with the regulation of serine/threonine kinase activity by cAMP. Some of these kinases specifically phosphorylate cellular structural proteins, such as histone, laminins, etc. Others phosphorylate still more kinases, resulting in either the activation or deactivation of downstream protein kinases. Specific examples in which serine/threonine kinases elicit specific cellular responses are discussed in this chapter. 

Ahn, N. G., Weiel, J. E., Chan, C. P., and Krebs, E. G. (1990). Identification of multiple epidermal growth factor-stimulated protein serine/threonine kinases from Swiss 3T3 cells. J. Biol. Chem. 265 11487-11494. 

Nakielny, S., Cohen, P., Wu, J., and Sturgill, T. (1992a). MAP kinase activator from insulin-stimulated skeletal muscle is a protein serine/threonine kinase. EMBO S. 11 2123-2129. 

EC5 Isamerases transfer groups within molecules to yield isomeric forms. (EC 5.1 - 5.5 5.99) EC5.1 Racemases and Epimerases (no-cardicin-A epimerase, protein-serine epimerase, etc.) sucrose H202 - 24... 

The functioning of G proteins may be influenced by phosphorylation. G proteins, as well as their associated receptors and RGS proteins, have been reported to undergo phosphorylation by a host of protein serine/ threonine kinases and protein tyrosine kinases. While the ramifications of receptor phosphorylation are becoming increasingly well understood (see Chs 23 and 24), the effect of phosphorylation of G proteins and RGS proteins, and its role in the regulation of physiological processes, have been more difficult to establish with certainty. This remains an important area of future investigation. 

Most protein serine-threonine kinases undergo autophosphorylation 399... 

The brain contains multiple forms of protein serine-threonine phosphatases 399... 

Protein serine-threonine phosphatases play a critical role in the control of cell function 400... 

Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation. These properties determine the functional roles played by the very large number of protein kinases that have been found in mammalian tissues, most of which are known to be expressed in neurons [3]. The major classes of protein serine-threonine kinase in the brain, listed in Table 23-1, are covered in this chapter. The major classes of protein tyrosine kinases in the brain are discussed in Chapter 24. 

TABLE 23-1 Major classes of protein serine-threonine kinases... 

The mitogen-activated protein kinase cascade is second-messenger-independent. Although the second-messenger-dependent protein kinases were identified first as playing an important role in neuronal function, we now know that many other types of protein serine-threonine kinase are also essential (Table 23-1). Indeed, one of the most critical discoveries of the 1990s was the delineation of the mitogen-activated protein kinase (MAP kinase or MAPK) cascades. 

Most protein serine-threonine kinases undergo autophosphorylation. The autophosphorylation of most protein kinases is associated with an increase in kinase activity [4, 10]. In some instances, such as with the RII subunit of PKA, autophosphorylation represents a positive feedback mechanism for kinase activation, in this case by enhancing the rate of dissociation of the RII and C subunits. In the case of CaMKII, autophosphorylation causes the catalytic activity of the enzyme to become independent of Ca2+ and calmodulin. This means that the enzyme, activated originally in response to elevated cellular Ca2+, remains active after Ca2+ concentrations have returned to baseline. By this mechanism, neurotransmitters that activate CaMKII can produce relatively long-lived alterations in neuronal function. In other instances, such as with the receptor-associated protein tyrosine kinases (discussed in Ch. 24), autophosphorylation is an obligatory step in the sequence of molecular events through which those kinases are activated and produce physiological effects. 

Protein dephosphorylation is catalyzed by phospho-hydrolases called protein phosphatases. While the number of protein tyrosine kinases is roughly comparable to the number of protein tyrosine phosphatases, protein serine-threonine kinases vastly outnumber the protein serine-threonine phosphatases, of which about 25 different species are known to exist. This relative under-representation may be accounted for by the alternative diversification... 

These enzymes are more closely related, in terms of their amino acid sequences, to protein tyrosine phosphatases than to protein serine-threonine phosphatases. 

Cohen, P. T. W. Novel protein serine/threoine phosphatases variety is the spice of life. Trends Biochem. Sci. 27 59-75, 1997. 

Price, N. E. and Mumby, M. C. Brain protein serine/ threonine phosphatases. Curr. Opin. Neurobiol. 9 336-342, 1999. 

Goldberg, J., Huang, H. B., Kwon,Y. G., Greengard, P., Nairn, A. C. and Kuriyan, J. Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1. Nature 376 745-753,1995. 

Gaudet, E.A., Huang, K.S., Zhang, Y., Huang, W., Mark, D., and Sportsman, J.R., A homogeneous fluorescence polarization assay adaptable for a range of protein serine/threonine and tyrosine kinases, ]. Biomol. Screen., 8,164, 2003. 

The cytotoxicities of okadaic acid as EC50 against the P388 and L1210 cell lines are 1.7 nano-molar and 17 nano-molar, respectively. Additionally, okadaic acid strongly inhibits protein serine/threonine phosphatase 1,2A,... 

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