Results Mathematical model selleckbio of EGFR ERK signaling in H1299 lung cancer cells To evaluate the dynamics of the signal transmission Inhibitors,Modulators,Libraries from EGFR to its downstream elements, we used the network model introduced by Kholodenko et al, Hatakeyama et al, and Wolf et al with some modifications. Figure 1 shows the EGFR signaling path way considered in the current study. The pathway starts from the EGFR located in the cell membrane and is composed of 27 reaction steps. EGF first binds to the EGFR and causes receptor dimerization, then receptor autophosphorylation occurs at particular tyrosine resi dues in the cytoplasmic domains. Phosphorylated EGFR is dephosphorylated by protein phosphotyrosine phosphatases. Some of the phosphorylated dimers are internalized by binding of Cbl and subsequently degraded.

This receptor degradation is one of the most important processes Inhibitors,Modulators,Libraries for preventing over signaling. Other phophorylated dimers associate with the Grb2 SOS complex via Shc. This complex can dissociate, yielding the EGFR dimer, the Grb2 SOS com plex, and Shc. After recruiting Grb2 SOS with the phosphorylated EGFR dimer to the plasma membrane, SOS activates Ras by exchanging GDP for GTP. In an opposing reaction, deactivation of Ras is accelerated by GAPs associated with EGFR. Binding of GAP to the phosphorylated EGFR is a key step Inhibitors,Modulators,Libraries to control the output of the signaling pathway. EGF stimulation induces recruitment of GAP to the membrane, and GAP is strongly activated after binding to the phosphorylated EGFR. Ras deactivation normally keeps its GTPase activity low.

The GTP bound Ras can then translocates Raf1 to the cell membrane for its activation, which is also reversible. Activated Raf1 activates MEK by phosphoryla tion of two serine residues, Inhibitors,Modulators,Libraries and the activated MEK phosphorylates ERK Inhibitors,Modulators,Libraries on threonine and tyrosine residues. The MAPK cascade is negatively regulated by PP2A for the dephosphorylation of MEK and by MKP3 for the dephosphorylation of ERK. After its translocation to the nucleus, activated ERK reg ulates gene expression by phosphorylating transcription factors such as Elk and Myc. To investigate cell specific EGFR signaling dynamics, we constructed an H1299WT model, an H1299EGFR WT model, and two alternate H1299L858R models. The differences among these models are summarized in Table 1.

To simulate the effect of EGFR overexpression in H1299EGFR WT and H1299L858R cells, the initial concentrations of EGFR in the respective models were selleckchem assumed to be higher than that in the WT model. Also, we constructed two L858R models based on H1299L858R cell specific characteristics. In the first model, Mig6 was added to the EGFR WT model because Mig6 is highly endogenously expressed in H1299L858R cells. For simplicity, the effect of Mig6 was not described explicitly, but was rea lized by modifying four parameters in the EGFR WT model.