Specificity Kinases

MAPK cascades are composed of three cytoplasmic kinases, the MAPKKK, MAPKK, and MAPK, that are regulated by phosphorylation (Fig. 1) [1, 2]. The MAPKKK, also called MEKK for MEK kinase, is a serine/threonine kinase. Selective activation of MAPKKKs by upstream cellular stimuli results in the phosphorylation of MAPKK, also called MEK for MAP/ERK kinase by the MAPKKK. MAPKKK members are structurally diverse and are differentially regulated by specific upstream stimuli. The MAPKK is phosphorylated by the MAPKKK on two specific serine/ threonine residues in its activation loop. The MAPKK family members are dual specificity kinases capable of phosphorylating critical threonine and tyrosine residues in the activation loop of the MAPKs. MAPKKs have the fewest members in the MAPK signaling module. MAPKs are a family of serine/threonine kinases that upon activation by their respective MAPKKs, are capable of phosphorylating cytoplasmic substrates as well as... 

The roles that Ca + and polyphosphoinositide breakdown products might play in hormone action are presented in Figure 43-6. In this scheme the activated protein kinase C can phosphorylate specific substrates, which then alter physiologic processes. Likewise, the Ca -cahnodulin complex can activate specific kinases. These then modify substrates and thereby alter physiologic responses. 

Besides these pathways, specific kinases like mixed lineage kinase and double-stranded RNA-activated protein kinase (PKR) have been implicated in gpl20-mediated neuronal death (Bodner et al. 2002 Alirezaei et al. 2007). 

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of P-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite P-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of... 

A novel class of tricyclic lymphocyte specific kinase (Lck) inhibitors containing the 9,10-dihydro-8//-pyrazolo[l,2-tf]pyrimido[4,5-c]pyridazin-8-one moiety has been reported <2006BML4257, 2006H(68)2037>. The most promising compound, 708, advanced to pharmacokinetic evaluation <2006BML4257>. 

The synthesis of 4-trifhioromethylpyrimido[4,5-c]pyridazin-5,7-diones from 6-hydrazinouracils and l,l,l-trifluoropropane-2,3-dione monohydrates has been reported <06H1875>. Novel pyrimido[4,5-c]pyridazines have been synthesized and investigated as inhibitors of lymphocyte specific kinase <06BMCL4257 06H2037>. 

The putative receptor for agrin is a RPTK known as muscle-specific kinase (MuSK). The extracellular domain of MuSK resembles that of the ROR family of RPTKs, while the kinase domain is similar to that of the Trk neurotrophic receptor (Fig. 24-6). MuSK is expressed at low concentrations in proliferating myoblasts and is induced... 

The PDHC catalyzes the irreversible conversion of pyruvate to acetyl-CoA (Fig. 42-3) and is dependent on thiamine and lipoic acid as cofactors (see Ch. 35). The complex has five enzymes three subserving a catalytic function and two subserving a regulatory role. The catalytic components include PDH, El dihydrolipoyl trans-acetylase, E2 and dihydrolipoyl dehydrogenase, E3. The two regulatory enzymes include PDH-specific kinase and phospho-PDH-specific phosphatase. The multienzyme complex contains nine protein subunits, including... 

LDL low density lipoprotein MuSK muscle-specific kinase... 

Neutrophil membranes contain inositol lipids, which comprise about 5-6% of the total membrane lipids. About 80% of these inositol lipids possess stearic acid (Cl8 0) at Cl and arachidonic acid (C20 4) at C2 positions. Phosphatidylinositol accounts for most of these lipids (90%), with smaller amounts of PIP (6%) and PIP 2 (4%), which are synthesised sequentially by the action of 4- and 5-specific kinases, respectively (see Fig. 6.6). Neutrophil membranes also possess a phosphatidylinositol-specific phospholipase C which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into Ins 1,4,5 P3 and DAG (Fig. 6.7). Both PLC-/3(/ 2) and PLC-y (72) families appear to be present in neutrophils. The coupling of receptor occupancy to PLC activation in neutrophils can be through a heterotrimeric G-protein, the mobile subunit of which has been termed G p. Evidence for this G-protein link comes from the following facts ... 

Control of pymvate dehydrogenase activity is via covalent modification a specific kinase causes inactivation of the PDH by phosphorylation of three serine residues located in the pyruvate decarboxylase/dehydrogenase component whilst a phosphatase activates PDH by removing the phosphates. The kinase and phosphatase enzymes are non-covalently associated with the transacetylase unit of the complex. Here again we have an example of simultaneous but opposite control of enzyme activity, that is, reciprocal regulation. 

Table 1. Current view of histone phosphorylation sites and specific kinases...

Based on their substrate specificity, kinases have been divided into two broad classes serine/threonine- and tyrosine-specific kinases. Of the estimated 500 kinases, roughly one-fifth of these are tyrosine kinases. The two classes are further broken down and grouped by function, required cofactors, and substrates. ... 

Table 1 Some known protein tyrosine, serine/threonine and dual specificity kinases...

Non-receptor serine/threonine kinases and dual specificity kinases cAMP-dependent protein kinase (PKA) Phosphoinositol-3-kinase (PI-3K) Cyclin-dependent kinase (CDK) Mitogen-activated protein kinase (MAPK) MAPKK (ERK)... 

Regarding the localization of the majority of proteasomes to the nuclear rim and nuclear envelope, it seems likely, that proteasomal degradation requires nuclear export or translocation processes, which directs nuclear proteins at least to the nuclear pore or to the inner surface of the nucleus. This implies that all components of the ubiquitination machinery have to be active inside the nucleus, v ich seems to be a prerequisite for the specific export process. It is also possible that nucleus-specific kinases or E2/E3 enzymes promote the triggering of nuclear proteins for rapid degradation. 

The ascaracide fenazaquin 1175 is active against several spider mite species, while DPC-083 (BMS 561390) 1176 is an anti-HIV reverse transcriptase inhibitor <2000JME2019>. The quinazoline 1177 has recently been identified as a lead compound for the development of selective inhibitors of lymphocyte-specific kinase (Lck) which is involved in T-cell-mediated autoimmune and inflammatory disease <2006JME5671>. 

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