k1 is the membrane asso ciated Lyn at basal level. k2 represents the rate at which activation of Lyn take place after the binding of agonist to the membrane receptor. k3 is the rate at which Syk is activated by the Lyn. d1 and d2 represents the amount of negative regulator on the active forms of Lyn and Syk respectively at their ground state. nificantly higher when the basal activity secondly of Lyn was lower. This finding would be consistent with the experi mental results Inhibitors,Modulators,Libraries obtained in the present study. To further delineate the effect of basal activity on receptor induced signaling, we plotted different peak values with respect to different basal values for Lyn and Syk by varying the parameter for negative regulator.

Figure 7C shows Inhibitors,Modulators,Libraries the result of the simulation where an inverse relation between basal level of Lyn activity, and the extent of its activation after BCR stimulation is clearly evident. To observe the effect of other parameters especially those acting on the active Syk species we performed a similar analysis on Syk. A similar qualitative behaviour with dif ferent slope values was again Inhibitors,Modulators,Libraries obtained. The results of our modeling analysis thus further sub stantiated our experimental results by highlighting the role played by the negative regulators of signal initiation, such as SHP 1, in determining the cell fate decision. Discussion B lymphocytes represent a good model system to study plasticity in receptor activated signaling processes, and the consequent influence on the cellular phenotypic response.

Depending on their state of maturation, anti gen encounter by the B lymphocytes can lead to varied outcomes that range from activation and or proliferation to anergy, or also to activation induced cell death through apoptotic mechanisms. In general, mature B lymphocytes Inhibitors,Modulators,Libraries undergo activation followed by proliferation upon induction of BCR dependent signal ing by an antigen. In contrast, engagement of the BCR induces AICD preceded by an arrest of the cell cycle in immature and transitional stage immature B cells. This latter process serves to eliminate self reactive B cells during its different stages of devel opment. Various cell lines such as WEHI 231, CH31, and B104 among others have been employed as models systems for the study of BCR signaling in imma ture B cells. In all of these cases, cell stimulation with a suitable surrogate antigen leads first to G1 cell cycle arrest, which is then followed by apoptosis.

Both the results presented here as well as those described in earlier studies confirm that CH1 cells represent yet another Inhibitors,Modulators,Libraries good model system for recapitu lating BCR driven responses in immature B cells. First, similar to immature and transition stage immature 17-AAG Tanespimycin B cells, CH1 cells also express high levels of the IgM class of the BCR, with little or no expression of those belong ing to the IgD class. In immature B cells, BCR activated cells fail to enter into the S phase and this effect can be reversed by treatment with IL4.