title: Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3.
abstract: The progression of cancers from primary tumors to invasive and metastatic stages accounts for the overwhelming majority of cancer deaths. Understanding the molecular events which promote metastasis is thus critical in the clinic. Translational control is emerging as an important factor in tumorigenesis. The messenger RNA (mRNA) cap-binding protein eIF4E is an oncoprotein that has an important role in cancer initiation and progression. eIF4E must be phosphorylated to promote tumor development. However, the role of eIF4E phosphorylation in metastasis is not known. Here, we show that mice in which eukaryotic translation initiation factor 4E (eIF4E) cannot be phosphorylated are resistant to lung metastases in a mammary tumor model, and that cells isolated from these mice exhibit impaired invasion. We also demonstrate that transforming growth factor-beta (TGFβ) induces eIF4E phosphorylation to promote the translation of Snail and Mmp-3 mRNAs, and the induction of epithelial-to-mesenchymal transition (EMT). Furthermore, we describe a new model wherein EMT induced by TGFβ requires translational activation via the non-canonical TGFβ signaling branch acting through eIF4E phosphorylation.
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Robichaud
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: S V
authors.initials: SV
authors.lastname: del Rincon
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Huor
authors.affiliation: Department of Biochemistry, Microbiology and Immunology, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Alain
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: L A
authors.initials: LA
authors.lastname: Petruccelli
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Hearnden
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Goncalves
authors.affiliation: Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Grotegut
authors.affiliation: Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Spruck
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: L
authors.identifier: 0000000218939812
authors.initials: L
authors.lastname: Furic
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: O
authors.identifier: 0000000314121308
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: W J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse