Protein tyrosine kinases dimerization

It is worth mentioning that membrane-bound forms of GC, which can be considered signal transducing enzymes , are structurally homologous to other signal transducing enzymes, such as certain protein tyrosine kinases and phosphatases, which also possess receptor moieties in their extracellular (amino terminus) domain and enzyme catalytic activity in their intracellular domain (see Ch. 24). Activation of many of these receptors occurs upon ligand-induced dimerization of the receptors, and a similar... 

Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription. 

Quinazolines are of great interest in the pharmaceutical industry as protein tyrosine kinase inhibitors. Dener et al 8 described a synthesis starting from 2-methoxybenzaldehyde, Wang, or Rink resins. With the aldehyde resin reductive aminations were undertaken to yield polymer-bound secondary amines (Fig. 7). The latter were subjected to 2,4-dichloro-6,7-dimethoxyquinazoline to give the 4-amino-substituted derivatives. These were then allowed to react with primary or secondary amines at 135-140° in the presence of DBU in DMA. As a result of a detailed scope and limitation study, Dener et al,28 note that some bifunctional amines, such as piperazine, give to some extent dimeric derivatives. 

Regarding the 1,3-diazocines, it was reported that the synthesis of the left domain of haplophytine, a hetero-dimeric alkaloid endowed with insecticidal activity, contained a pyrrolo-fused carbonyl bridged 1,3-benzodiazocine moiety <2007AG(E)4715>. It was also reported that the synthesis of a pyrazolo-fused 1,3-benzodiazocine and its activity as inhibitor of lymphocyte-specific protein tyrosine kinase (Lck) <2007W0026720>, and the thermal decomposition of a polynitro substituted 1,3-diazocine <2006RJGC499>. 

A Chinese isolate of Penicillium terrestre derived from sediments yielded a series of new gentisyl alcohol polymers, including the trimeric terrestriol A (89) and the dimeric terrestrols B-H (90-96)/° All compounds showed moderate cytotoxicity toward four different cancer cell lines as well as moderate radical scavenging activity in the DPPH assay. Furthermore, 95 displayed moderate inhibitory activity against protein tyrosine kinases Src and KDR. 

Two receptor classes, cytokine receptors and receptor tyrosine kinases, transduce signals via their associated or intrinsic protein tyrosine kinases. Ligand binding triggers formation of functional dimeric receptors and phosphorylation of the activation lip in the kinases, enhancing their catalytic activity (see Figure 14-5). 

The insulin receptor is a dimeric receptor tyrosine kinase that can initiate the Ras-MAP kinase pathway, leading to changes in gene expression. Insulin stimulation also can initiate the PT3 kinase pathway just described, leading to activation of protein kinase B. In insulin-stimulated liver, muscle, and fat cells, activated protein kinase B acts in several ways to lower blood glucose and promote glycogen synthesis. 

Activation of the protein tyrosine kinase occurs after dimerization of growth factor receptors. This arises from transautophosphorylation. Unphosphorylated protein tyrosine kinase domains have low enzymic activity, but when they are brought into proximity to each other by receptor dimerization, they can phosphorylate each other. The effect is to convert them to a high-activity state. 

For proteins such as tyrosine-kinase receptors, dimerization (the association of two receptors to form a new species... 

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