Other protein kinases

As indicated above, there may be as many as a thousand PKs encoded by the human genome. In addition to the Ser/Thr PKs described above, there are other PKs that have been 

Translation can be inhibited through the phosphorylation of eukaryote initiation factor 2 (eIF2) by dsRNA-dependent PK (activated by viral dsRNA as a consequence of viral infection), by hemin-inhibited PK (activated in the absence of hemin in reticulocytes) and by GCN2 kinase (general control non-derepressible kinase) (activated by amino acid starvation and excess free tRNA). Phosphorylation of RNA polymerase II is a key process in the regulation of transcription (Chapter 9). 

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Src tyrosine kinase contains both an SH2 and an SH3 domain linked to a tyrosine kinase unit with a structure similar to other protein kinases. The phosphorylated form of the kinase is inactivated by binding of a phosphoty-rosine in the C-terminal tail to its own SH2 domain. In addition the linker region between the SH2 domain and the kinase is bound in a polyproline II conformation to the SH3 domain. These interactions lock regions of the active site into a nonproductive conformation. Dephosphorylation or mutation of the C-terminal tyrosine abolishes this autoinactivation. 

CREB stands for cyclic-AMP response element (CRE) binding protein and is a transcription factor. When phosphorylated by cyclic AMP- and cyclic GMP-dependent Protein Kinases or other protein kinases it binds to gene promoters that contain a specific binding site. After binding, the respective transcription activity is modulated. 

Ras activates a number of pathways among them is the mitogen-activated protein (MAP) kinases, which transmit signals downstream to other protein kinases and gene regulatory proteins... 

HSFl phosphorylation must be sensitive to nonheat inducers of HSF-DNA binding activity because HSFl phosphorylation can be achieved at 37 °C by other inducers of the HS response. HSF 1 contains polypeptide sequences that could serve as substrates for well characterized protein kinases, but few of these are known to be heat inducible. One family of protein kinases, the S6 protein kinases, have already been shown to exhibit heat inducible activity however, their peak level of activity during HS occurs well after the maximal induction of HSF phosphorylation (Jurivich et al., 1991). Thus, other protein kinases are likely to be directly linked to the phosphorylation of HSF. Some of the putative protein phosphorylation sites on HSF include motifs for protein kinase C, casein kinase, and enterokinase. There are tyrosine sequences that match substrates for known tyrosine kinases, but whether these residues are accessible to phosphorylation is not established. 

Tyrosine kinase activation can also initiate a phosphorylation and dephosphorylation cascade that involves the action of several other protein kinases and the counter-... 

Protein kinase B, or Akt, was discovered as the product of an oncogene of the acutely transforming retrovirus AKT8, causing T-cell lymphomas in mice. It encodes a fusion product of a cellular serine/threonine protein kinase and the viral structural protein Gag. This kinase is similar to both protein kinase Ce (PKCe 73% identity to the catalytic domain) and protein kinase A (PKA 68%). It differs from other protein kinases in that it contains a pleckstrin homology (PH) domain, which allows it to bind to polyphosphoinositide head groups (and also to G-protein fly subunits). To date, three subtypes have been identified a, (3, and y, all of which show a broad tissue distribution. It... 

There are several mechanisms involved in the vasodilator effect of flavonoids. The main mechanism seems to be related to the inhibition of protein kinase C or some of the processes activated by this protein. The inhibition of other protein kinases and cyclic nucleotide phosphodiesterase activity and blockage of calcium entry can also contribute to this effect to a greater or lesser extent (Alvarez Castro and Orallo, 2003 Herrera and others 1996). Certain flavonoids, like the flavonol myricetin, have a two-phase action on blood vessels vasoconstrictor in lowest active concentrations and vasodilator in higher concentrations (Alvarez Castro and Orallo, 2003). 

Not included are other protein kinases present in diverse tissues, including brain, that play a role in generalized cellular processes, such as intermediary metabolism, and that may not play a role in neuron-specific phenomena. CAK, CDK-activating kinase ... 

Protein kinases phosphorylated by other protein kinases (many examples)... 

Other protein kinases may indirectly influence the activation of NF-kappap. For example, in contrast to the pro-inflammatory effects typically observed with activation of kinases, the elevation ofcAMP activates PKA and blocks transcription of iNOS mRNA [51,178, 229, 230]. Astrocytes contain a variety of NT receptors that are coupled to Gs-adenylate cyclase [231] and, either activation of P-adrenergic/dopamine receptors or employing agents that increase cAMP, such as forskolin (adenylate cyclase activator), PDE inhibitors [i.e. pentoxifylline], dibutyrl cAMP, or 8-bromo cAMP can attenuate lipopolysaccharide (LPS)/cytokine activated iNOS mRNA in microglia, astrocytes and a number of other cell types [51,176,177,178, 232-237]. In contrast, agents that suppress the intracellular concentration of cAM P such as H-89 and Rp-cAM P are pro-... 

Around the same time as bioinformatics revealed similarities between CSN, proteasome, and eIF3, Dubiel and coworkers, while trying to identify new components of the 26S proteasome, identified a novel protein complex that possessed protein kinase activity. They found that the new protein complex was capable of phosphor-ylating c-jun and IkKBq and the precursor of NFk-B was called pl05. Other protein kinases are found to interact with CSN as well. For example, inositol 1,3,4,-trisphosphate 5/6 kinase, casein kinase 2, and protein kinase D associate with CSN. " ... 

Insulins (see p. 388), growth factors, and cytokines (see p. 392), for example, act via 1-helix receptors. Binding of the signaling substance leads to activation of internal kinase activity (in some cases, dimerization of the receptor is needed for this). The activated kinase phosphorylates itself using ATP (auto-phosphorylation), and also phosphorylates tyrosine residues of other proteins (known as receptor substrates). Adaptor proteins that recognize the phosphotyrosine residues bind to the phosphorylated proteins (see pp. 388, 392). They pass the signal on to other protein kinases. 

Vertex has reported several variations of the pyrazole class with activity against Aurora-A and a number of other protein kinases [174-187]. Patent applications covering (lH-pyrazol-3-yl)quinazohnes (73a,b) and a series exemplified by 74 were described as having protein kinase inhibitor activity... 

Studies similar to the substrate specificity studies outlined for oAMP-dependent protein kinase have already begun for other protein kinases such as cGMP-dependent protein kinase ( ), phos-jAiorylase kinase (69-71) and two tyrosine-specific protein kinases (72-75). 

There are many other protein kinases that do not show any close relationship to these subfamilies. These include protein kinases with two-fold specificity, in that they can phosphorylate Ser/Thr and also Tyr residues. An example of a protein kinase with twofold specificity is the MAP kinase kinase (see Chapter 10). 

Many protein kinases require phosphorylation of Ser/Thr or Tyr residues to reach full activity. The activating phosphorylation often takes place in a part of the structure in the vicinity of the active center, known as the activation segment which spans two conserved sequence motifs (DFG to APE, using single-letter code) present im almost all kinases (review Johnson et al., 1996). Phosphorylation of the activation segment may be catalyzed by other protein kinases or by the protein kinase s own active center. In the latter case, this is generally an autophosphorylation in trans, i.e., between the subunits of an oligomeric protein kinase (see Chapter 8.1.3). 

Of the protein kinases, protein kinase A is the best investigated and characterized (review Francis and Corbin, 1994). The functions of protein kinase A are diverse. Protein kinase A is involved in the regulation of metabolism of glycogen, lipids and sugars. Substrates of protein kinase A may be other protein kinases, as well as enzymes of intermediary metabolism. Protein kinase A is also involved in cAMP-stimulated transcription of genes that have a cAMP-responsive element in their control region (review Montminy, 1997). An increase in cAMP concentration leads to activation of protein kinase A which phosphorylates the transcription factor CREB at Ser 133. CREB only binds to the transcriptional coactivator CBP in the phosphorylated state and stimulates transcription (see Chapter 1.4.4.2). 

The A kinase anchor proteins (AKAP), which are tightly associated with the cytoskeleton, serve as anchors for protein kinase A. In addition to the RII subimit of protein kinase A, the AKAP proteins also bring protein phosphatases and other protein kinases to the cytoskeleton in a targeted fashion. The AKAP79 protein binds protein kinase C and protein phosphatase 2B (calcineurin) as well as the RII subunit. The possibility to bring both a protein kinase and a protein phosphatase to the same place in the cell opens up the prospect of a coordinated and layered regulation of both enzyme activities. 

Receptor tyrosine kinases are integral membrane proteins that have a hgand-binding domain on the extracellular side and a tyrosine kinase domain on the cytosohc side (see Fig. 8.1). The transmembrane portion is made up of just one structural element thus it is assumed that it crosses the membrane in an a-hehcal form. On the cytoplasmic side, in addition to the conserved tyrosine kinase domain, there are also further regulatory sequence portions at which autophosphorylation, and phosphorylation and dephosphorylation by other protein kinases and by protein phosphatases, can take place. 

In addition to Raf kinase activation, Ras protein also mediates stimulation of other protein kinases, known as MEK kinases. These are signal proteins in the MARK pathway (see Chapter 10) and transmit signals at the level of gene expression. 

The MAPK/ERK proteins are at the lower end of signal transduction within a MAPK module and are generally preceded by two other protein kinases (Fig. 10.2). The MAPK/ERK proteins receive the signal in the form of an activating phosphorylation by a preceding protein kinase known as MAP/ERK kinase (MEK) or also MAP kinase kinase (MAPKK). 

Activation of MEK kinases occurs particularly via proteins of the Ras superfamUy (p21-Ras, Rho/Rac proteins). However, other pathways for activation of MEK kinases, e.g., via other protein kinases such as protein kinase C or PAK (p21 activated kinase) (review Marshall, 1995 Robinson and Cobb, 1997) have also been reported. 

Fig. 13.8. Structure of the inactive form of CDK2 in humans. The crystal structure of the human CDK2 apoenzyme shows a very similar folding topology to protein kinase A and other protein kinases (see Chapter 7). The occurrence of the aL12 element is specific for CDK2 this interferes with binding of ATP and substrate in the active form.

The ATM protein has been identified as an important member of a reaction chain that leads from detection of DNA damage to activation of the p53 protein. Mutations of the ATM protein are causally associated with the disease ataxia telangiectasia, thus the name ATM (ataxia telangiectasia mutated). The ATM protein has protein kinase activity and is counted as a member of the PI3-kinase family, due to sequence homologies (review Canman et al., 1998). The p53 protein is phosphorylated at Serl5 by ATM kinase (Canman et al., 1998) and it is assumed that this phosphorylation contributes to activation of the p53 protein. The ATM protein is preceded by other protein kinases that are directly or indirectly activated by DNA damage and pass this signal on to the p53 protein via the ATM protein. 

In the analysis of the structural data of other protein kinases, it is noted that only cAPK has been crystallized with its specific peptide inhibitor. Nevertheless, three other structures of protein kinases compared with the structure of the cAPK-PKI complex provide substantial evidence for the conservation of the substrate binding cleft. The substrate binding cleft of the phosphorylase kinase structure has been analyzed in detail and it is clear that all amino acids of the known specific substrate can be built into the PKI model and all required corresponding charges can be found in the cleft of the phosphorylase kinase structure. In the CK-1 structure determined without a peptide, the requirement of the peptide specificity resides on the P-3 site, which has to be phosphorylated. An analysis of the surface charges of the cleft of the CK-1 structure reveals the exact correspondence of the residues required to interact with a phosphorylated substrate at this site. 

RNA Strand Initiation and Promoter Clearance TFIIH has an additional function during the initiation phase. A kinase activity in one of its subunits phosphorylates Pol II at many places in the CTD (Fig. 26-9). Several other protein kinases, including CDK9 (cyclin-dependent kinase 9), which is part of the complex pTEFb (positive transcription elongation/actor b), also phosphorylate the... 

Phosphorylated IRS promotes activation of other protein kinases and phosphatases, reading to biologic actions of insulin. 

Apart from PKA, some other protein-kinases were found to be controlled by forskolin, such as cytosolic sphingosine kinase in rat periosteal cells [186] and protein kinase B (PKB) [187]. The latter was found to be stimulated by the activation of PKA through a PI3 (phosphatidylinositol 3)-kinase-independent pathway. Furthermore, a distinct activation mechanism was suspected, other than that normally observed by growth factors such as insulin, since substitution of the serine at the S473 position of PKB with alanine could not prevent activation by forskolin. The JAK family of protein kinases in T lymphocytes can also be regulated by forskolin through the activation of PKA [188]. Thus it seems obvious that many other enzymes could be susceptible to control by forskolin. 

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