Insider information: how palmitoylation of Ras makes it a signaling double agent.
Ras small guanosine triphosphatases (GTPases) are involved in the regulation of cell growth, differentiation, and survival and are mutated in as many as 30% of human cancers. These proto-oncogenic GTPases are mostly involved in the activation of signaling cascades downstream from growth factor receptors and lead to transcriptional activation of specific genes. Because of a complex series of posttranslational COOH-terminal modifications, Ras proteins are found on various intracellular membranes, in addition to the plasma membrane. Using a novel fluorescent probe monitoring GTP-bound Ras in live cells (GFP-Raf-1-RBS), Golgi-associated H-Ras was shown to be activated in situ after growth factor stimulation, with kinetics distinct from that of H-Ras activation at the plasma membrane. Furthermore and also noteworthy, an oncogenic H-Ras chimera that was tethered to the endoplasmic reticulum activated the extracellular signal-regulated kinase (ERK) and Akt pathways preferentially, whereas a Golgi-tethered oncogenic H-Ras chimera activated predominantly the Jun-NH2-terminal kinase (JNK) pathway. Thus, the subcellular localization of Ras influenced which downstream effector pathways were engaged. The activation of Golgi-H-Ras may be mediated by second messengers through the action of a Golgi-localized guanine nucleotide exchange factor, Ras-GRP.
D000818:Animals; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology; D019308:Palmitic Acid / Q000737:chemistry*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000737:chemistry* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D008565:Membrane Proteins; D019308:Palmitic Acid; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)