title: Axl phosphorylates Elmo scaffold proteins to promote Rac activation and cell invasion.
abstract: The receptor tyrosine kinase Axl contributes to cell migration and invasion. Expression of Axl correlates with metastatic progression in cancer patients, yet the specific signaling events promoting invasion downstream of Axl are poorly defined. Herein, we report Elmo scaffolds to be direct substrates and binding partners of Axl. Elmo proteins are established to interact with Dock family guanine nucleotide exchange factors to control Rac-mediated cytoskeletal dynamics. Proteomics and mutagenesis studies reveal that Axl phosphorylates Elmo1/2 on a conserved carboxyl-terminal tyrosine residue. Upon Gas6-dependent activation of Axl, endogenous Elmo2 becomes phosphorylated on Tyr-713 and enters into a physical complex with Axl in breast cancer cells. Interfering with Elmo2 expression prevented Gas6-induced Rac1 activation in breast cancer cells. Similarly to blocking of Axl, Elmo2 knockdown or pharmacological inhibition of Dock1 abolishes breast cancer cell invasion. Interestingly, Axl or Elmo2 knockdown diminishes breast cancer cell proliferation. Rescue of Elmo2 knockdown cells with the wild-type protein but not with Elmo2 harboring Tyr-713-Phe mutations restores cell invasion and cell proliferation. These results define a new mechanism by which Axl promotes cell proliferation and invasion and identifies inhibition of the Elmo-Dock pathway as a potential therapeutic target to stop Axl-induced metastases.
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada Département de Médecine (Programmes de Biologie Moléculaire), Université de Montréal, Montreal, QC, Canada.
authors.forename: Afnan
authors.initials: A
authors.lastname: Abu-Thuraia
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Gauthier
authors.affiliation: Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montreal, QC, Canada.
authors.forename: Rony
authors.initials: R
authors.lastname: Chidiac
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Screaton
authors.affiliation: Département de Pharmacologie, Université de Montréal, Montreal, QC, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Gratton
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada Département de Médecine (Programmes de Biologie Moléculaire), Université de Montréal, Montreal, QC, Canada Département de Biochimie, Université de Montréal, Montreal, QC, Canada Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada jean-francois.cote@ircm.qc.ca.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016296:Mutagenesis; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C099818:DOCK1 protein, human; C486678:ELMO2 protein, human; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D020744:rac GTP-Binding Proteins; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human