Activation of RalA is critical for Ras-induced tumorigenesis of human cells.
RalGEFs were recently shown to be critical for Ras-mediated transformed and tumorigenic growth of human cells. We now show that the oncogenic activity of these proteins is propagated by activation of one RalGEF substrate, RalA, but blunted by another closely related substrate, RalB, and that the oncogenic signaling requires binding of the RalBP1 and exocyst subunit effector proteins. Knockdown of RalA expression impeded, if not abolished, the ability of human cancer cells to form tumors. RalA was also commonly activated in a panel of cell lines from pancreatic cancers, a disease characterized by activation of Ras. Activation of RalA signaling thus appears to be a critical step in Ras-induced transformation and tumorigenesis of human cells.
Lim
Kian-Huat
KH
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Baines
Antonio T
AT
Fiordalisi
James J
JJ
Shipitsin
Michail
M
Feig
Larry A
LA
Cox
Adrienne D
AD
Der
Channing J
CJ
Counter
Christopher M
CM
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D033921:Vesicular Transport Proteins; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020726:ral Guanine Nucleotide Exchange Factor / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; C470182:EXOC2 protein, human; D020690:GTPase-Activating Proteins; C095637:RALBP1 protein, human; D034741:RNA, Small Interfering; C483163:Ralb protein, human; D033921:Vesicular Transport Proteins; D020726:ral Guanine Nucleotide Exchange Factor; D006160:Guanosine Triphosphate; C492198:RALA protein, human; C419867:RHOF protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020725:ral GTP-Binding Proteins; D020741:rho GTP-Binding Proteins