Zyxin regulates migration of renal epithelial cells through activation of hepatocyte nuclear factor-1β

Hepatocyte nuclear factor-1 beta (HNF-1 beta) is an epithelial tissue-specific transcription factor that regulates gene expression in the kidney, liver, pancreas, intestine, and other organs. Mutations of HNF-1 beta in humans produce renal cysts and congenital kidney anomalies. Here, we identify the LIM-domain protein zyxin as a novel binding partner of HNF-1 beta in renal epithelial cells. Zyxin shuttles to the nucleus where it colocalizes with HNF-1 beta. Immunoprecipitation of zyxin in leptomycin B-treated cells results in coprecipitation of HNF-1 beta. The protein interaction requires the second LIM domain of zyxin and two distinct domains of HNF-1 beta. Overexpression of zyxin stimulates the transcriptional activity of HNF-1 beta, whereas small interfering RNA silencing of zyxin inhibits HNF-1 beta-dependent transcription. Epidermal growth factor (EGF) induces translocation of zyxin into the nucleus and stimulates HNF-1 beta-dependent promoter activity. The EGF-mediated nuclear translocation of zyxin requires activation of Akt. Expression of dominant-negative mutant HNF-1 beta, knockdown of zyxin, or inhibition of Akt inhibits EGF-stimulated cell migration. These findings reveal a novel pathway by which extracellular signals are transmitted to the nucleus to regulate the activity of a transcription factor that is essential for renal epithelial differentiation.