Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation.
Ral proteins (RalA and RalB) comprise a distinct family of Ras-related GTPases (Feig and Emkey, 1993). Recently, Ral-GDS, the exchange factor that activates Ral proteins, has been shown to bind specifically to the activated forms of RasH, R-Ras and Rap1A, in the yeast two-hybrid system. Here we demonstrate that although all three GTPases have the capacity to bind Ral-GDS in mammalian cells, only RasH activates Ral-GDS. Furthermore, although constitutively activated Ra1A does not induce oncogenic transformation on its own, its expression enhances the transforming activities of both RasH and Raf. Finally, a dominant inhibitory form of RalA suppresses the transforming activities of both RasH and Raf. These results demonstrate that activation of Ral-GDS and thus its target, Ral, constitutes a distinct downstream signaling pathway from RasH that potentiates oncogenic transformation.
Urano
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Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Emkey
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R
Feig
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LA
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002522:Chlorocebus aethiops; D000939:Epitopes; D019204:GTP-Binding Proteins / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D015398:Signal Transduction; D020725:ral GTP-Binding Proteins
D000939:Epitopes; D010455:Peptides; D011518:Proto-Oncogene Proteins; C082190:Ralb protein, rat; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019204:GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras); D020725:ral GTP-Binding Proteins