The Molecular Perspective: The ras Oncogene

delivering protein messages. These proteins—hor mones, growth factors, chemokines, etc.—are far too large to enter the receiving cell, so an elaborate mechanism of signal transduction has been developed, to transmit messages from the cell surface into the cell nucleus, where the topic of conversation is implemented as a change in gene expression. As one might imagine, mutation of proteins within these signal transduction pathways has disastrous consequences. If the message is altered, the cell may get a false message to proliferate, leading to cancer. For this reason, the genes of many signal transduction proteins were first discovered in their role as oncogenes —genes that lead to cell transformation when mutated—before their functions in normal cells were elucidated. The ras oncogenes were among the first to be discovered. The Ras proteins deliver signals from cell surface receptors, such as growth factor receptors, G-protein coupled receptors that recognize molecules such as thrombin and bradykinin, and integrins. These signals are then passed protein-to-protein along several different pathways, ultimately effecting mitogenic functions such as lipid metabolism, DNA synthesis, and cytoskeletal organization. Disruption of these signals through mutation of the rasgene is involved in many tumor types, including roughly half of all colon cancers and 90% of pancreatic carcinomas. The Ras protein sits at the center of a many-tiered cascade of molecular interactions. Most of the proteins along this cascade are activated by phosphorylation, but Ras uses a bound guanine nucleotide to toggle between its “on” and “off” states. Normally, Ras binds GDP in its neutral state. A message is passed from the receptor to Ras by guanine nucleotide exchange factors (GEFs) that expel this GDP, allowing GTP, which is more plentiful in the cytoplasm, to bind in its place. GTP causes a subtle rearrangement of the protein, which then triggers a cascade of mitogen-activated protein kinases. These kinases ultimately phosphorylate the target, such as a transcription factor, delivering the message to its final destination. This signal is necessarily self-limiting. Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off,” and a collection The Molecular Perspective: The ras Oncogene