Sec5 and Exo84 foster oncogenic ras-mediated tumorigenesis.
The genes encoding the Ras family of small GTPases are mutated to yield constitutively active GTP-bound oncogenic proteins in one third of all human cancers. Oncogenic Ras binds to and activates a number of proteins that promote tumorigenic phenotypes, including the family of Ral guanine nucleotide exchange factors (RalGEF). Activated RalGEFs convert the Ral family of small GTPases, composed of RalA and RalB, from an inactive GDP-bound state to an active GTP-bound state. As both RalA and RalB have been implicated in a variety of tumorigenic phenotypes, we sought to determine which proteins downstream of Rals promote transformation and tumorigenesis. Here, we report that shRNA-mediated knockdown of the Ral effector proteins Sec5 and Exo84, but less so in the case of RalBP1, reduced oncogenic RalGEF-mediated transformation and oncogenic Ras-driven tumorigenic growth of human cells. These results suggest that Rals promote oncogenic Ras-mediated tumorigenesis through, at least in part, Sec5 and Exo84.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, DUMC-3813, Durham, NC 27710, USA.
Sameer H
SH
Issaq
Kian-Huat
KH
Lim
Christopher M
CM
Counter
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009857:Oncogenes / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; C470182:EXOC2 protein, human; C480857:EXOC8 protein, human; D020690:GTPase-Activating Proteins; C095637:RALBP1 protein, human; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; D020725:ral GTP-Binding Proteins; D018631:ras Proteins