title: Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration.
abstract: Cell migration is essential throughout embryonic and adult life. In numerous cell systems, the small GTPase Rac is required for lamellipodia formation at the leading edge and movement ability. However, the molecular mechanisms leading to Rac activation during migration are still unclear. Recently, a mammalian superfamily of proteins related to the prototype member Dock180 has been identified with homologues in Drosophila and Caenorhabditis elegans. Here, we addressed the role of Dock180 and ELMO1 proteins, which function as a complex to mediate Rac activation, in mammalian cell migration. Using mutants of Dock180 and ELMO1 in a Transwell assay as well as transgenic rescue of a C. elegans mutant lacking CED-5 (Dock180 homologue), we identified specific regions of Dock180 and ELMO1 required for migration in vitro and in a whole animal model. In both systems, the Dock180.ELMO1 complex formation and the ability to activate Rac were required. We also found that ELMO1 regulated multiple Dock180 superfamily members to promote migration. Interestingly, deletion mutants of ELMO1 missing their first 531 or first 330 amino acids that can still bind and cooperate with Dock180 in Rac activation failed to promote migration, which correlated with the inability to localize to lamellipodia. This finding suggests that Rac activation by the ELMO.Dock180 complex at discrete intracellular locations mediated by the N-terminal 330 amino acids of ELMO1 rather than generalized Rac activation plays a role in cell migration.
authors.affiliation: Beirne Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Grimsley
authors.forename: Jason M
authors.initials: JM
authors.lastname: Kinchen
authors.forename: Annie-Carole
authors.initials: AC
authors.lastname: Tosello-Trampont
authors.forename: Enrico
authors.initials: E
authors.lastname: Brugnera
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Haney
authors.forename: Mingjian
authors.initials: M
authors.lastname: Lu
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Doris
authors.initials: D
authors.lastname: Klingele
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hengartner
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017173:Caenorhabditis elegans; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D019143:Evolution, Molecular; D005838:Genotype; D005982:Glutathione Transferase / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D009154:Mutation; D010587:Phagocytosis; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C099818:DOCK1 protein, human; C465214:ELMO1 protein, human; D006160:Guanosine Triphosphate; D005982:Glutathione Transferase; D020744:rac GTP-Binding Proteins