Phosphorylation regulates the subcellular location and activity of the snail transcriptional repressor.
The Snail gene product is a transcriptional repressor of E-cadherin expression and an inducer of the epithelial-to-mesenchymal transition in several epithelial tumor cell lines. This report presents data indicating that Snail function is controlled by its intracellular location. The cytosolic distribution of Snail depended on export from the nucleus by a CRM1-dependent mechanism, and a nuclear export sequence (NES) was located in the regulatory domain of this protein. Export of Snail was controlled by phosphorylation of a Ser-rich sequence adjacent to this NES. Modification of this sequence released the restriction created by the zinc finger domain and allowed nuclear export of the protein. The phosphorylation and subcellular distribution of Snail are controlled by cell attachment to the extracellular matrix. Suspended cells presented higher levels of phosphorylated Snail and an augmented extranuclear localization with respect to cells attached to the plate. These findings show the existence in tumor cells of an effective and fine-tuning nontranscriptional mechanism of regulation of Snail activity dependent on the extracellular environment.
Domínguez
David
D
Unitat de Biologia Cel.lular i Molecular, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
Montserrat-Sentís
Bàrbara
B
Virgós-Soler
Ariadna
A
Guaita
Sandra
S
Grueso
Judit
J
Porta
Montserrat
M
Puig
Isabel
I
Baulida
Josep
J
Francí
Clara
C
García de Herreros
Antonio
A
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D013347:Subcellular Fractions; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000097606:Exportin 1 Protein
D004268:DNA-Binding Proteins; D028884:Karyopherins; D007930:Leucine; D019913:Nuclear Localization Signals; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D012694:Serine; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000097606:Exportin 1 Protein