title: Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2.
abstract: Epithelial cell migration is crucial for the development and regeneration of epithelial tissues. Aberrant regulation of epithelial cell migration has a major role in pathological processes such as the development of cancer metastasis and tissue fibrosis. Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. Failure to degrade RAPGEF2 in epithelial cells results in sustained activity of Rap1 and inhibition of cell migration induced by HGF, a potent metastatic factor. Furthermore, expression of a degradation-resistant RAPGEF2 mutant greatly suppresses dissemination and metastasis of human breast cancer cells. These findings reveal a molecular mechanism regulating migration and invasion of epithelial cells and establish a key direct link between IKKβ and cell motility controlled by Rap-integrin signaling.
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Roberto
authors.initials: R
authors.lastname: Magliozzi
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; The Netherlands Proteomics Center, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Teck Yew
authors.initials: TY
authors.lastname: Low
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
authors.forename: Bart G M W
authors.initials: BG
authors.lastname: Weijts
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Tianhong
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Emma
authors.initials: E
authors.lastname: Spanjaard
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; The Netherlands Proteomics Center, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Shabaz
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: Department of Physiological Chemistry and Center for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: van Veen
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: de Rooij
authors.affiliation: Department of Physiological Chemistry and Center for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: Fried J T
authors.initials: FJ
authors.lastname: Zwartkruis
authors.affiliation: Department of Physiological Chemistry and Center for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; The Netherlands Proteomics Center, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands. Electronic address: d.guardavaccaro@hubrecht.eu.
authors.forename: Daniele
authors.initials: D
authors.lastname: Guardavaccaro
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001943:Breast Neoplasms; D048128:Casein Kinase Ialpha / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C403525:RAPGEF2 protein, human; C586377:RAPGEF2 protein, zebrafish; D029961:Zebrafish Proteins; D044843:SKP Cullin F-Box Protein Ligases; D048128:Casein Kinase Ialpha; D051550:I-kappa B Kinase