Histone kinases protein kinase

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. 

Mercuric chloride has also been shown to inhibit the enzymatic activity of soluble protein kinase A from mice brain, apparently by binding to sulphydryl groups of the enzyme [111]. The inhibition was of a non-competitive type with respect to HI histone. 

Histone H3 (Til) phosphorylation occurs during mitosis by Dlk/ZIP kinase (Dlk Death-associated protein (DAP)-like kinase, ZIP Zipper interacting protein kinase) (Preuss et al, 2003) (Table 1). Histone H3 at Serine 28 is phosphorylated by Aurora B kinase at mitosis and this phosphorylation coincides with chromosome condensation (Goto et al., 1999, Goto et al, 2002) (Fig. 2), (Table 1). Histone H3 (S28) phosphorylation initiates at prophase, whereas histone H3 (SIO) phosphorylation initiates during the late G2 phase (Hendzel et al, 1997). 

Ge Z, Liu C, Bjorkholm M, Gruber A, Xu D (2006) Mitogen-activated protein kinase cascade-mediated histone H3 phosphorylation is critical for telomerase reverse transcriptase expression/telomerase activation induced by proliferation. Mol Cell Biol 26(l) 230-237 Giet R, Glover DM (2001) Drosophila aurora B kinase is required for histone H3 phosphorylation and condensin recruitment during chromosome condensation and to organize the central spindle during cytokinesis. J Cell Biol 152(4) 669-682... 

SI39 (for mammals). The responsible kinases are members from phosphatidyli-nositol 3-kinase (PI3K)-like family kinases, which include ataxia telangiectasia mutated (ATM), AT-related (ATR), and DNA dependent protein kinase (DNA-PK) (Burma et al, 2001 Stiff et al, 2004 van Attikum and Gasser, 2005). Histone H2AX phosphorylation is directly related to repair of damaged chromatin (for details see chapter on Role of histone phosphorylation in chromatin dynamics and its implication in diseases ). 

Histone kinases responsible for N-phosphorylation have been isolated from regenerating rat liver [109] and Walker-256 carcinosarcoma cells [110]. One kinase with a pH optimum of 9.5 phosphorylated His-18 and His-75 of H4, while the other with a pH optimum of 6.5 phosphorylated lysine of HI. The enzyme from regenerating rat liver phosphorylated H4 at 1-phosphoryl histidine, while the carcinosarcoma enzyme phosphorylated H4 His at the position 3 [111]. Both kinases were cAMP independent [110]. Matthews and colleagues purified a 32-kDa histidine H4 kinase from yeast, Saccharomyces cerevisiae [112,113]. The enzyme phosphorylated His-75 (1-phosphoryl histidine) in H4. His-18 of H4 and other histidines in other core histones were not phosphorylated by this kinase [112]. Protein phosphatases 1, 2A, and 2C could dephosphorylate His-75 of H4 [114]. Applying a gel kinase approach to detect mammalian H4 histidine kinases, Besant and Attwood detected four activities in the 34-41 kDa range with extracts from porcine thymus [115]. 

The temporal sequence of H3 and H4 methylation after synthesis has been examined in Ehrlich ascites tumor cells [144] and trout testis [149]. Methylation lagged histone synthesis, and the histone was methylated after being bound to DNA. H4 methylation follows the stepwise acetylations and deacetylations [149]. It was suggested that methylation was involved in final arrangement of H3 and H4 on newly replicated DNA [144] and might be involved in histone interactions with other proteins such as histone kinases [149]. 

The potential substrates for histone phosphorylation include N-terminal serine and threonine hydroxyl groups of H2A, H3, and H4 the N- and C-terminal tails of HI and the unique C-terminal of H2AX [19,29] (see Fig. 6). Similar to acetylation, phosphorylation appears to be a dynamic modification that transduces on/off signals to nuclear modulators. Enzymes implicated in regulating this pathway include the cyclin-dependent kinases and mitogen activated protein kinases, and the antagonistic phosphatase 1 [158,159]. 

Prelich, G. and Winston, F. (1993) Mutations that suppress the deletion of an upstream activating sequence in yeast involvement of a protein kinase and histone H3 in repressing transcription in vivo. Genetics 135, 665-676. 

Histone HI Laminin Protein kinases Transcription factors... 

The TAFs fulfill numerous functions (Review Burley and Boeder, 1996 Struhl and Moqtaderi, 1998). On the one hand they are ascribed a structure promoting function. Some of the TAFs display a high degree of homology to the histones H2A, H3 and H4, and it is speculated that they help to create a nucleosome-like structure at the promotor. Furthermore, the TAFs are targets for protein-protein interactions with transcriptional activators. TAFs also posses enzymatic activity. TAF11250 has both a histone acetylase activity and a protein kinase activity. While the former presumable plays a role in the reorganization of the nucleosome, the latter can lead to phosphorylation of TFIIF. 

The TAFs are components of TFIID (see table 1.1) and are required for a regulated transcription (review Verriijzer and Tijan 1996, Bmley and Roeder, 1996 ). Thus, the stimulation of transcription by the transcriptional activators Spl and NTF-1 depends upon the presence of specific TAFs in the TFllD complex. The TAFs mediate interactions between the transcriptional activators and the TFllD complex in many cases direct protein-protein interactions could be demonstrated between the activators and TAFs. Some of the TAFs possess additional enzymatic activities which allow them to participate in the regulation of transcription. By this token, the histone acetylase and protein kinase activity of TAFn250 is ascribed a regulatory function in the remodeling of chromatin and in the control of the activity of the basal transcription factors. 

Many protein kinases show indistinct substrate specificity, especially in in vitro experiments. Certain phosphorylation sites of the histone HI can be phosphorylated by various protein kinases. Insight into the specificity requirements of protein kinases was only possible once highly resolved structural information on the binding of model substrates to protein kinases was available (see 7.1.4). 

As morusin (3) was assumed to interact with the phorbol ester receptor, we examined whether it inhibited the activation of protein kinase C by teleocidin in vitro [73]. Fig. (9) shows that morusin (3) inhibited the phosphorylation of histone type III-S by protein kinase C dose-dependent and that 80 pmol/L morusin caused 50% inhibition. 

Discuss the roles of the following proteins in development receptors, transcription factors, protein kinases, histones, DNA methylases, adhesion molecules, ubiquitin. How do small RNA molecules participate in development ... 

Many other kinases have been studied, often in the context of regulation of some process by phosphorylation and dephosphorylation. Examples from muscle regulation have already been given. A further example is the transcription of eukaryotic DNA, which may be regulated by phosphorylation of non-histone chromosomal proteins. A number of nuclear protein kinases have been partially purified. These have an absolute requirement for divalent cations, and are not stimulated by 3, 5 -cyclic AMP (cAMP).287,288... 

A number of endogenous substrate proteins have been identified for protein kinase C in various cell types. These include nuclear proteins, histones, high mobility group proteins, enzymes such as tyrosine hydroxylase and guanylate cyclase, ri-... 

The molecular basis for regulation of enzymatic activity through phosphorylation and dephosphorylation has been established in many enzyme systems (29). The significance of these reactions in histones, ribosomal proteins and KNA polymerase is not known. In an attempt to establish the specificity of the cyclic AMP-dependent protein kinases, the structure of several substrates have been determined (30). The data indicate that the sequence around the phosphorylated serine residue all contain two basic amino acids separated by no more than two residues from the N-terminal of the susceptible serine (e.g. -Arg-Arg-X-Y-Ser-). 

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