RAS Pathway v3.0?
, by Frank McCormick
Frank McCormick directs the scientific activities of the NCI RAS Initiative at the Frederick National Laboratory for Cancer Research.
Two years ago I asked for your input on what genes comprise the "RAS Pathway". You responded with many suggestions that we incorporated into "v2.0" of the pathway, shown below. I'm happy to say that we relied heavily on your suggestions including collecting, synthesizing (when necessary), validating (according to TCGA) and sequencing all 180 genes in the v2 pathway. Through the community’s valuable input and the hard work of Dom Esposito and the Frederick National Laboratory for Cancer Research (FNLCR) RAS Reagents Group, the genes are now available through Addgene, in both the stop and no-stop versions. Considering that at least 20% of the ORF clones were either not available at all or were mis-annotated, this represents a significant contribution to our joint efforts to better understand how mutant RAS genes cause cancer.
Now, I think it's time we take another look at the pathway to determine if a version 3.0 is needed. What have we learned in the past two years about what genes and proteins modulate and feed into the RAS pathway? Are there any new genes to include for v3.0? Are there any in v2.0 that are less relevant now?
The diagram shows 118 genes arranged in 36 groups containing one to eleven genes per group. The proteins represented by gene names in a group are thought to carry out similar, but probably not identical, functions. Gene names separated by periods represent proteins believed to form physical complexes. At the top of the diagram "growth factors" signal through receptors and messengers to the three RAS proteins. The RAS proteins in turn signal through three alternative pathways to affect many downstream targets including TP53, RB1, and MTOR. Arrows represent activation signals, dotted "T" lines represent inhibitory signals. The bracket connecting KSR1 and KSR2 to the RAF, MAP2K, and MAPK genes represents a scaffolding function.
As always, we welcome your suggestions for changes in the pathway diagram. Provide your feedback by commenting below or email me at SolveRAS@nih.gov.