Abl, phosphorylation

While imatinib is efficacious in treating Philadelphia chromosome positive CML, it is not as effective a treatment for patients with Philadelphia chromosome positive ALL [47]. As a prelude to clinical investigation, AMN107 was studied for its effect on Bcr-Abl positive ALL cell lines [48]. In prohferation and Bcr-Abl phosphorylation assays with two patient-derived ALL cell hnes, namely Z-119 and Z-181, AMN107 was 30-40-fold more potent than imatinib. 

Fig. 10.1-6 Biosensor for c-Abl phosphorylation of c-Crk-II. c-Abl phosphorylates Tyr221 of c-Crk-ll, which induces an intramolecular association with the SH2 domain. This rearrangement yields...

Woodring PJ et al (2004) c-Abl phosphorylates Dokl to promote filopodia during cell spreading. J Cell Biol 165 493-503... 

PTB domains recognize small peptides containing a phosphotyrosine, usually with the consensus sequence, NPXpY. Some PTB-containing proteins, such as Numb, are able to bind to the consensus peptide in the absence of phosphorylated tyrosine, suggesting phosphotyrosine is dispensable for the function of certain PTB domains. Hydrophobic residues N-termi-nal to the phosphotyrosine provide some specificity of target and distinction from SH2 domains. PTB domains appear to be particularly important in docking... 

From this observation of the inhibition by adenosine, and other observations, Newell and Tucker suspected the existence of a common synthetic pathway for adenosine and thiamine, and proved (with the help of a collection of mutants) that the bifurcation occurred after the 5-amino- l-(P-D-ribofura-nosyl)imidazole 5 -phosphate (46) step (Scheme 23). Finally, they found that 5-amino-l-(0-D-ribofuranosyl)imidazole (47), labeled with l4C in the imidazole ring, was incorporated into pyramine without significant loss of molar radioactivity by a mutant that is able to use this nucleoside (presumably after phosphorylation).53,54... 

The lower trialky Itin compounds are able to inhibit mitochondrial, oxidative phosphorylation (471,477) and, therefore, disrupt the funda-... 

Figure 38-7. Activation of elF-4E by insulin and formation of the cap binding elF-4F complex. The 4F-cap mRNA complex is depicted as in Figure 38-6. The 4F complex consists of elF-4E (4E), elF-4A, and elF-4G. 4E is inactive when bound by one ofa family of binding proteins (4E-BPs). Insulin and mitogenic factors (eg, IGF-1, PDGF, interleukin-2, and angiotensin II) activate a serine protein kinase in the mTOR pathway, and this results in the phosphorylation of 4E-BP. Phosphorylated 4E-BP dissociates from 4E, and the latter is then able to form the 4F complex and bind to the mRNA cap. These growth peptides also phosphorylate 4E itself by activating a component of the MAP kinase pathway. Phosphorylated 4E binds much more avidly to the cap than does nonphosphorylated 4E.

Stable heterologous complexes are not necessary to explain the limited P-enolpyr-uvate-dependent mannitol phosphorylation kinetic data now available from domain complementation assays transient complexes between domains are sufficient. The challenge remains, however, to visualize how a subcloned A or B domain would be able to transiently associate with an A or B domain on an dimer or tetramer,... 

S. typhimurium normally transport trehalose via the galactose permease and are able to grow on this substrate in the complete absence of PTS phosphorylating activity. However, in S. typhimurium which lack a functional galactose permease, IfMan appears to be able to transport trehalose [78]. There is no evidence that trehalose is phosphorylated in this process, again pointing to Il "-dependent transport in the facilitated diffusion mode. 

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