title: Zyxin regulates migration of renal epithelial cells through activation of hepatocyte nuclear factor-1β.
abstract: Hepatocyte nuclear factor-1β (HNF-1β) is an epithelial tissue-specific transcription factor that regulates gene expression in the kidney, liver, pancreas, intestine, and other organs. Mutations of HNF-1β in humans produce renal cysts and congenital kidney anomalies. Here, we identify the LIM-domain protein zyxin as a novel binding partner of HNF-1β in renal epithelial cells. Zyxin shuttles to the nucleus where it colocalizes with HNF-1β. Immunoprecipitation of zyxin in leptomycin B-treated cells results in coprecipitation of HNF-1β. The protein interaction requires the second LIM domain of zyxin and two distinct domains of HNF-1β. Overexpression of zyxin stimulates the transcriptional activity of HNF-1β, whereas small interfering RNA silencing of zyxin inhibits HNF-1β-dependent transcription. Epidermal growth factor (EGF) induces translocation of zyxin into the nucleus and stimulates HNF-1β-dependent promoter activity. The EGF-mediated nuclear translocation of zyxin requires activation of Akt. Expression of dominant-negative mutant HNF-1β, 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.
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Yun-Hee
authors: YH
authors: Choi
authors: Brian T
authors: BT
authors: McNally
authors: Peter
authors: P
authors: Igarashi
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D020798:Two-Hybrid System Techniques; D060589:Zyxin / Q000235:genetics / Q000378:metabolism*
chemical_list: C496496:Hnf1b protein, mouse; D047428:Protein Kinase Inhibitors; C498285:Zyx protein, mouse; D060589:Zyxin; D051539:Hepatocyte Nuclear Factor 1-beta; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP
keywords: cell motility; epidermal growth factor; protein-protein interactions; transcription
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