Our model revealed a strong influence of the receptor proxi mal negative regulator, which gen erally balances against positive signals to ensure system homeostasis. By using this model we could confirm that as the basal activation of Lyn increased, due to reduced activity of SHP 1, the sensitivity of this kinase to the BCR also diminished. As a result, transmission of signal Bosutinib molecular weight to the downstream intermediates was also nega tively affected at least when measured at the level of Syk activation. At one level these latter findings served to rationalize the sparse character of the BCR signaling network in CH1 cells and, by extension, immature B lymphocytes. Inhibitors,Modulators,Libraries In addition to this however, we believe that our revela tion of the importance of the basal state of the signaling machinery in defining sensitivity, and thereby Inhibitors,Modulators,Libraries the cellu lar response, to the activation of cell surface also has important bearings from a broader point of view.

Thus, differences in the basal phosphorylation state of at least the early signaling intermediates could well explain how variations in the response to the same external stimulus are Inhibitors,Modulators,Libraries generated from cells that differ either at the level of tissue type, or activation state. Background The ErbB family receptors belong to the receptor tyro sine kinases and consist of four members. ErbB1, ErbB2, ErbB3 and ErbB4. EGFR is distributed various tissues of the human body, and plays a cri tical role in the regulation of a variety of cellular responses ranging from cell differentiation, growth, pro liferation, apoptosis, migration and adhesion.

EGFR is frequently overexpressed in various human tumors including non small cell lung cancer and is associated with poor outcome. In many cases, enhanced EGFR signaling leads to abnormal cellu lar processes and often induces cancer. Certain NSCLC patients have mutations at specific amino acid residues in the kinase Inhibitors,Modulators,Libraries domain of EGFR and show altered responsiveness to gefitinib, an EGFR tyrosine kinase inhibitor. The L858R substitution is one of the most Inhibitors,Modulators,Libraries frequently reported mutations and shows good responses to gefitinib. It was reported that the L858R mutation enhances gefitinib sensitivity due to a structural change in the kinase domain resulting in an increased binding affinity of gefitinib for its ATP binding pocket in vitro.

On the other hand, a large scale binding assay using different types of kinases showed that the difference in binding affinity of the EGFR itself may not have a great effect on gefitinib sensitivity. Based on these observations, we speculated that other unknown factors affect gefitinib sensitivity in vivo rather than alteration of the binding research use affinity. So far, cells with the L858R mutated EGFR have been reported to have two characteristics. First, Mig6 is highly expressed in the L858R mutated EGFR cells.