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Over the last several years, epithelial-mesenchymal transition (EMT), a process in which cells undergo a switch from an epithelial phenotype to a mesenchymal phenotype, has emerged as important not only in embryonic development, but also as a potential mechanism for cancer progression. Epithelial cells are characterized by cell-cell interactions, with the formation of tight junctions, lateral, apical, and basal membranes, polarized distribution of cellular components, and lack of mobility, whereas mesenchymal cells have loose interaction with other cells, are not polarized, and can be motile. In order for a cell to undergo EMT, a number of dramatic cellular and molecular changes must take place. These changes include: dissolution of adherens junctions, reorganization of the actin cytoskeleton, loss of apical-basal polarity, induction of promesenchymal gene expression, and migration through basement membranes and tissues. In this review, we describe the molecular components that drive the transformation of normal cells to tumor cells, with an emphasis on the complex signaling networks that underlie EMT. We then examine how each of these players might mediate the transformation of lung epithelial cells induced by tobacco smoke.

Bacterial flagellin can interact with both Toll-like receptor 5 (TLR5) and the cell surface glycolipid, asialoGM1, to activate an innate immune response. The induction of mucin by flagellin in human lung epithelial cells (NCIH292) is dependent on asialoGM1 ligation, ATP receptor signaling, Ca2+ mobilization, and Erk1/2 activation. Conversely, the activation of NF-kappaB by flagellin is dependent on signaling through TLR5. These results prompted us to ask whether the flagellin-induced TLR5 signaling pathway was intersecting with or mutually independent of the nucleotide receptor pathway activated downstream of asialoGM1. Herein, we demonstrate that the release of ATP induced by flagellin is dependent on a Toll signaling cascade. Although Toll was able to activate NF-kappaB in the absence of extracellular ATP, Toll required ATP to activate Erk1/2. These results suggest interdependence between the asialoGM1 and TLR5 pathways and reveal a previously unsuspected role for autocrine extracellular ATP signaling in TLR signaling.

Mucin production is an evolutionarily ancient defense mechanism that is retained in mammals and operates at all mucosal surfaces to protect the host against pathogens and irritants. As in lower organisms, the mammalian mucosa (epithelium) produces mucin in response to diverse insults. Our studies aim to understand the intracellular signaling and gene regulation mechanisms mediating mucin production in response to clinically important insults. To date, we find that the signaling pathway triggered by each type of insult is distinct. Relatively common, however, is the involvement of the protein tyrosine kinase c-Src, the MAP kinase kinase MEK 1/2, and the transcription factor NF-kappaB. Basbaum C, Lemjabbar H, Longphre M, Li D, Gensch E, McNamara N. Control of mucin transcription by diverse injury-induced signaling pathways.