title: Ral activation promotes melanomagenesis.
abstract: Up to one-third of human melanomas are characterized by an oncogenic mutation in the gene encoding the small guanosine triphosphatase (GTPase) NRAS. Ras proteins activate three primary classes of effectors, namely, Rafs, phosphatidyl-inositol-3-kinases (PI3Ks) and Ral guanine exchange factors (RalGEFs). In melanomas lacking NRAS mutations, the first two effectors can still be activated through an oncogenic BRAF mutation coupled with a loss of the PI3K negative regulator PTEN. This suggests that Ras effectors promote melanoma, regardless of whether they are activated by oncogenic NRas. The only major Ras effector pathway not explored for its role in melanoma is the RalGEF-Ral pathway, in which Ras activation of RalGEFs converts the small GTPases RalA and RalB to an active guanosine triphosphate-bound state. We report that RalA is activated in several human melanoma cancer cell lines harboring an oncogenic NRAS allele, an oncogenic BRAF allele or wild-type NRAS and BRAF alleles. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of RalA, and to a lesser extent of RalB, variably inhibited the tumorigenic growth of melanoma cell lines having these three genotypes. Thus, as is the case for Raf and PI3 K signaling, Rals also contribute to melanoma tumorigenesis.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Zipfel
authors.forename: D C
authors.initials: DC
authors.lastname: Brady
authors.forename: D F
authors.initials: DF
authors.lastname: Kashatus
authors.forename: B D
authors.initials: BD
authors.lastname: Ancrile
authors.forename: D S
authors.initials: DS
authors.lastname: Tyler
authors.forename: C M
authors.initials: CM
authors.lastname: Counter
mesh_terms: D000483:Alleles; D048708:Cell Growth Processes / Q000235:genetics; D011905:Genes, ras; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C483163:Ralb protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins