title: The proto-oncogene Fgr regulates cell migration and this requires its plasma membrane localization.
abstract: Fgr participates in integrin signaling in myeloid leukocytes. To examine the role of its specific domains in regulating cell migration, we expressed various Fgr molecules in COS-7 cells. Full-length, membrane-bound Fgr, but not an N-terminal truncation mutant that distributed to an intracellular compartment, increased cell migration on fibronectin and enhanced phosphorylation of the p85 subunit of phosphatidylinositol 3-kinase (PI3K), cortactin and focal adhesion kinase (FAK) at Y397 and Y576. Fgr increased Rac GTP loading, and phosphorylation of the Rac GEF Vav2, and bound to a protein complex formed by the Rho inhibitor p190RhoGAP and FAK, increasing p190RhoGAP phosphorylation, in a manner absolutely dependent on membrane localization. A kinase-defective truncation mutant of Fgr increased cell migration, albeit to a much lower extent than full-length Fgr, and was found to associate with the plasma membrane, to activate Rac and to form complexes with p190RhoGAP/FAK. Formation of complexes between p190RhoGAP, Fgr, and the FAK-related protein Pyk2 were also detected in murine macrophages. These findings suggest that the proto-oncogene Fgr regulates cell migration impinging on a signaling pathway implicating FAK/Pyk2 and leading to activation of Rac and the Rho inhibitor p190RhoGAP.
authors.affiliation: Department of Pathology, Section of General Pathology, University of Verona, Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Continolo
authors.forename: Anna
authors.initials: A
authors.lastname: Baruzzi
authors.forename: Meytham
authors.initials: M
authors.lastname: Majeed
authors.forename: Elena
authors.initials: E
authors.lastname: Caveggion
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Giorgio
authors.initials: G
authors.lastname: Berton
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002522:Chlorocebus aethiops; D051356:Cortactin; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015151:Immunoblotting; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D019061:src-Family Kinases
chemical_list: D051356:Cortactin; D005353:Fibronectins; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D049452:Green Fluorescent Proteins; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D019061:src-Family Kinases; C495869:Cttn protein, mouse; C496051:Ptk2 protein, mouse; C053102:proto-oncogene proteins c-fgr