Epidermal growth factor receptor mutation in combination with expression of MIG6 alters gefitinib sensitivity.

BACKGROUND: Epidermal growth factor receptor (EGFR) signaling plays an important role in the regulation of cell proliferation, survival, metastasis, and invasion in various tumors. Earlier studies showed that the EGFR is frequently overexpressed in non-small-cell lung cancer (NSCLC) and EGFR mutations at specific amino acid residues in the kinase domain induce altered responsiveness to gefitinib, a small molecule EGFR tyrosine kinase inhibitor. However, the mechanism underlying the drug response modulated by EGFR mutation is still largely unknown. To elucidate drug response in EGFR signal transduction pathway in which complex dynamics of multiple molecules involved, a systematic approach is necessary. In this paper, we performed experimental and computational analyses to clarify the underlying mechanism of EGFR signaling and cell-specific gefitinib responsiveness in three H1299-derived NSCLC cell lines; H1299 wild type (H1299WT), H1299 with an overexpressed wild type EGFR (H1299EGFR-WT), and H1299 with an overexpressed mutant EGFR L858R (H1299L858R; gefitinib sensitive mutant). RESULTS: We predicted and experimentally verified that Mig6, which is a known negative regulator of EGFR and specifically expressed in H1299L858R cells, synergized with gefitinib to suppress cellular growth. Computational analyses indicated that this inhibitory effect is amplified at the phosphorylation/dephosphorylation steps of MEK and ERK. CONCLUSIONS: Thus, we showed that L858R receptor mutation in combination with expression of its negative regulator, Mig6, alters signaling outcomes and results in variable drug sensitivity.

Mutation of epidermal growth factor receptor is associated with MIG6 expression.

Controlled activation of epidermal growth factor receptor (EGFR) is systematically guaranteed at the molecular level; however, aberrant activation of EGFR is frequently found in cancer. Transcription induced by EGFR activation often involves the coordinated expression of genes that positively and negatively regulate the original signaling pathway; therefore, alterations in EGFR kinase activity may reflect changes in gene expression associated with the pathway. In the present study, we investigated transcriptional changes after EGF stimulation with or without the EGFR kinase inhibitor Iressa in H1299 human non-small-cell lung cancer cells [parental H1299, H1299 cells that overexpress wild-type EGFR (EGFR-WT) and mutant H1299 cells that overexpress EGFR where Leu858 is substituted with Arg (L858R)]. The results obtained clearly demonstrate differences in transcriptional activity in the absence or presence of EGFR kinase activity, with genes sharing the same molecular functions showing distinct expression dynamics. The results show the particular enrichment of EGFR/ErbB signaling-related genes in a differentially expressed gene set, and significant protein expression of MIG6/RALT(ERRFI1), an EGFR negative regulator, was confirmed in L858R. High MIG6 protein expression was correlated with basal EGFR phosphorylation and inversely correlated with EGF-induced extracellular signal-regulated protein kinase phosphorylation levels. Investigation of the NCI-60 cell lines showed that ERRFI1 expression was correlated with EGFR expression, regardless of tissue type. These results suggest that cells accumulate MIG6 as an inherent negative regulator to suppress excess EGFR activity when basal EGFR kinase activity is considerably high. Taking all the above together, an EGFR mutation can cause transcriptional changes to accommodate the activation potency of the original signaling pathway at the cellular level.

A mathematical design of vector vaccine against autoimmune disease.

Viruses have been implicated in the initiation, progression, and exacerbation of several human autoimmune diseases. Evidence also exists that viruses can protect against autoimmune disease. Several proposed mechanisms explain the viral effects. One mechanism is "molecular mimicry" which represents a shared immunologic epitope with a microbe and the host. We consider, using a simple mathematical model, whether and how a viral infection with molecular mimicry can be beneficial or detrimental for autoimmune disease. Furthermore, we consider the possibility of development of a vector therapeutic vaccine that can relieve autoimmune disease symptoms. Our findings demonstrate that vaccine therapy success necessitates (i) appropriate immune response function, (ii) appropriate affinities with self and non-self antigen, and (iii) a replicative vector vaccine. Moreover, the model shows that the viral infection can cause autoimmune relapses.