title: Src activates Abl to augment Robo1 expression in order to promote tumor cell migration.
abstract: Cell migration is an essential step in cancer invasion and metastasis. A number of orchestrated cellular events involving tyrosine kinases and signaling receptors enable cancer cells to dislodge from primary tumors and colonize elsewhere in the body. For example, activation of the Src and Abl kinases can mediate events that promote tumor cell migration. Also, activation of the Robo1 receptor can induce tumor cell migration. However, while the importance of Src, Abl, and Robo1 in cell migration have been demonstrated, molecular mechanisms by which they collectively influence cell migration have not been clearly elucidated. In addition, little is known about mechanisms that control Robo1 expression. We report here that Src activates Abl to stabilize Robo1 in order to promote cell migration. Inhibition of Abl kinase activity by siRNA or kinase blockers decreased Robo1 protein levels and suppressed the migration of transformed cells. We also provide evidence that Robo1 utilizes Cdc42 and Rac1 GTPases to induce cell migration. In addition, inhibition of Robo1 signaling can suppress transformed cell migration in the face of robust Src and Abl kinase activity. Therefore, inhibitors of Src, Abl, Robo1 and small GTPases may target a coordinated pathway required for tumor cell migration.
authors.affiliation: Molecular Biology Department, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.
authors.forename: P Raaj
authors.initials: PR
authors.lastname: Khusial
authors.affiliation: Molecular Biology Department, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.|Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Vadla
authors.affiliation: Molecular Biology Department, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.|Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Krishnan
authors.affiliation: Department of Biochemistry and Program in Structural Biology, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Trudy F
authors.initials: TF
authors.lastname: Ramlall
authors.affiliation: Molecular Biology Department, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Genetcis Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Vascular Biology Center, Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Geng
authors.affiliation: Molecular Biology Department, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016374:Oncogene Proteins v-abl / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*; D000097905:Roundabout Proteins
chemical_list: D009419:Nerve Tissue Proteins; D016374:Oncogene Proteins v-abl; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D019061:src-Family Kinases; D000097905:Roundabout Proteins