Plasma membrane ion fluxes and NFAT-dependent gene transcription contribute to c-met-induced epithelial scattering.
Hepatocyte growth factor (HGF) signaling drives epithelial cells to scatter by breaking cell-cell adhesions and causing them to migrate as solitary cells, a process that parallels epithelial-mesenchymal transition. HGF binds and activates the c-met receptor tyrosine kinase, but downstream signaling required for scattering remains poorly defined. We have applied a chemical biology approach to identify components of HGF signaling that are required for scattering in an in vitro model system. This approach yields a number of small molecules that block HGF-induced scattering, including a calcium channel blocker. We show that HGF stimulation results in sudden and transient increases in ion channel influxes at the plasma membrane. Although multiple channels occur in the membranes of our model system, we find that TrpC6 is specifically required for HGF-induced scattering. We further demonstrate that HGF-induced ion influxes through TrpC6 channels coincide with a transient increase in nuclear factor of activated T-cells (NFAT)-dependent gene transcription and that NFAT-dependent gene transcription is required for HGF-induced cell scattering.
Department of Physiology and Developmental Biology, Brigham Young University, 574 WIDB, Provo, UT 84606,  USA.
Peter R
PR
Langford
Lance
L
Keyes
Marc D H
MD
Hansen
D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D007477:Ions / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D000199:Actins; D007477:Ions; D050778:NFATC Transcription Factors; D054852:Small Molecule Libraries; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D002118:Calcium