title: Abl Kinases Regulate HGF/Met Signaling Required for Epithelial Cell Scattering, Tubulogenesis and Motility.
abstract: Tight regulation of receptor tyrosine kinases (RTKs) is crucial for normal development and homeostasis. Dysregulation of RTKs signaling is associated with diverse pathological conditions including cancer. The Met RTK is the receptor for hepatocyte growth factor (HGF) and is dysregulated in numerous human tumors. Here we show that Abl family of non-receptor tyrosine kinases, comprised of Abl (ABL1) and Arg (ABL2), are activated downstream of the Met receptor, and that inhibition of Abl kinases dramatically suppresses HGF-induced cell scattering and tubulogenesis. We uncover a critical role for Abl kinases in the regulation of HGF/Met-dependent RhoA activation and RhoA-mediated actomyosin contractility and actin cytoskeleton remodeling in epithelial cells. Moreover, treatment of breast cancer cells with Abl inhibitors markedly decreases Met-driven cell migration and invasion. Notably, expression of a transforming mutant of the Met receptor in the mouse mammary epithelium results in hyper-activation of both Abl and Arg kinases. Together these data demonstrate that Abl kinases link Met activation to Rho signaling and Abl kinases are required for Met-dependent cell scattering, tubulogenesis, migration, and invasion. Thus, inhibition of Abl kinases might be exploited for the treatment of cancers driven by hyperactivation of HGF/Met signaling.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Ran
authors.initials: R
authors.lastname: Li
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Knight
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Departments of Biochemistry and Oncology, McGill University, Montreal, QC, Canada.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Pendergast
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004285:Dogs; D004847:Epithelial Cells / Q000502:physiology*; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D016315:Proto-Oncogene Proteins c-abl