Gli1 acts through Snail and E-cadherin to promote nuclear signaling by beta-catenin.
The Hedgehog pathway transcription factor Gli1 induces transformation of epithelial cells via induction of Snail, a repressor of E-cadherin (E-cad). E-cad is normally complexed with beta-catenin at the cell membrane. Loss of E-cad during developmental epithelial-mesenchymal transitions can switch beta-catenin from its role at adherens junctions to its role in nuclear transcription. During tumorigenesis it is unclear which pathways trigger this switch. In the current study, gain- and loss-of-function approaches identified E-cad as a selective inhibitor of transformation by Gli1, and Snail knockdown was rescued by downregulation of E-cad. Gli1 induced relocalization of beta-catenin from the cell membrane to the nucleus. The ability of wild-type or mutant alleles of E-cad to modulate transformation by Gli1 correlated with their ability to regulate localization of beta-catenin. Inhibition of Wnt-beta-catenin signaling by dominant negative Tcf4 selectively blocked in vitro transformation by Gli1. In Gli1-transgenic mice, infiltrating skin tumor cells expressed active, unphosphorylated beta-catenin. Our studies identify E-cad as a selective suppressor of transformation by Gli1 and point to the Sonic Hedgehog-Gli1 pathway as a key regulator of the beta-catenin switch in epithelial cells and cancers.
Li
X
X
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-3300, USA.
Deng
W
W
Lobo-Ruppert
S M
SM
Ruppert
J M
JM
D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000494:pharmacology; D004847:Epithelial Cells; D007668:Kidney; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism* / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000378:metabolism*
D015820:Cadherins; D004268:DNA-Binding Proteins; C498521:Gli1 protein, rat; D051741:Kruppel-Like Transcription Factors; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; C491192:Tcf4 protein, rat; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin