title: Type III TGFβ receptor and Src direct hyaluronan-mediated invasive cell motility.
abstract: During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. This process requires epithelial to mesenchymal transition (EMT) and directed cellular invasion. The Type III Transforming Growth Factor-beta Receptor (TGFβR3) is required for epicardial cell invasion and coronary vessel development. Using primary epicardial cells derived from Tgfbr3(+/+) and Tgfbr3(-/-) mouse embryos, high-molecular weight hyaluronan (HMWHA) stimulated cellular invasion and filamentous (f-actin) polymerization are detected in Tgfbr3(+/+) cells, but not in Tgfbr3(-/-) cells. Furthermore, HMWHA-stimulated cellular invasion and f-actin polymerization in Tgfbr3(+/+) epicardial cells are dependent on Src kinase. Src activation in HMWHA-stimulated Tgfbr3(-/-) epicardial cells is not detected in response to HMWHA. RhoA and Rac1 also fail to activate in response to HMWHA in Tgfbr3(-/-) cells. These events coincide with defective f-actin formation and deficient cellular invasion. Finally, a T841A activating substitution in TGFβR3 drives ligand-independent Src activation. Collectively, these data define a TGFβR3-Src-RhoA/Rac1 pathway that is essential for hyaluronan-directed cell invasion in epicardial cells.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Allison
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States.
authors.forename: Daniella
authors.initials: D
authors.lastname: Espiritu
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Joey V
authors.initials: JV
authors.lastname: Barnett
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States; Southwest Environmental Health Sciences Center, University of Arizona, Tucson, AZ 85721, United States; Steele Children's Research Center, University of Arizona, Tucson, AZ 85721, United States; Sarver Heart Center, University of Arizona, Tucson, AZ 85721, United States; Bio5 Institute, University of Arizona, Tucson, AZ 85721, United States.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Camenisch
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects; D019943:Amino Acid Substitution; D000818:Animals; D019393:Arrestin / Q000737:chemistry / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D006820:Hyaluronic Acid / Q000494:pharmacology*; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism; D010496:Pericardium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D011509:Proteoglycans / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D019393:Arrestin; C581598:Cdc42 protein, mouse; D009479:Neuropeptides; D011509:Proteoglycans; D034741:RNA, Small Interfering; C484602:Rac1 protein, mouse; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan; D006820:Hyaluronic Acid; D019061:src-Family Kinases; C526380:RhoA protein, mouse; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: EMT; Epicardium; Hyaluronan; Src kinase; Type III TGFβ receptor