title: ADP-ribosylation factor 6 regulates tumorigenic and invasive properties in vivo.
abstract: This study shows that the small GTP-binding protein ADP-ribosylation factor 6 (ARF6) is an important regulator of tumor growth and metastasis. Using spontaneous melanoma tumor growth assays and experimental metastasis assays in nude mice, we show that sustained activation of ARF6 reduces tumor mass growth but significantly enhances the invasive capacity of tumor cells. In contrast, mice injected with tumor cells expressing a dominantly inhibitory ARF6 mutant exhibited a lower incidence and degree of invasion and lung metastasis compared with control animals. Effects on tumor growth correlate with reduced cell proliferation capacity and are linked at least in part to alterations in mitotic progression induced by defective ARF6 cycling. Furthermore, phospho-ERK levels in subcultured cells from ARF6(GTP) and ARF6(GDP) tumor explants correlate with invasive capacity. ARF6-induced extracellular signal-regulated kinase (ERK) signaling leads to Rac1 activation to promote invadopodia formation and cell invasion. These findings document an intricate role for ARF6 and the regulation of ERK activation in orchestrating mechanisms underlying melanoma growth, invasion, and metastases.
authors.affiliation: Department of Biological Sciences, Freimann Life Science Center, and W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Vandhana
authors.initials: V
authors.lastname: Muralidharan-Chari
authors.forename: Holly
authors.initials: H
authors.lastname: Hoover
authors.forename: James
authors.initials: J
authors.lastname: Clancy
authors.forename: Jill
authors.initials: J
authors.lastname: Schweitzer
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.forename: Valerie
authors.initials: V
authors.lastname: Schroeder
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Castellino
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Schorey
authors.forename: Crislyn
authors.initials: C
authors.lastname: D'Souza-Schorey
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D051379:Mice; D010739:Phospholipase D / Q000378:metabolism
chemical_list: D000089982:ADP-Ribosylation Factor 6; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D010739:Phospholipase D; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse