Oncogenic Mutations of Ras

Oncogenic mutations of the ras gene lead to changes in the structure of the ras protein that, in turn, cause an increase in the level of the ras·GTP complex within the cells. There are two classes of oncogenic mutations in ras. Those that decrease GTPase activity and those that decrease nucleotide affinity.

The GTPase activity of the ras protein is part of the mechanism for turning the signaling pathway off. Thus slowing this reaction will cause an increase in the level of ras·GTP. This results in "turning on" the signal transducing pathway and ultimately, in tumors.

Mutations that decrease nucleotide affinity also cause an increase in the cellular levels of ras·GTP.  The amount of GTP bound to the ras protein is a complex function that depends on two factors:

• the affinity of the protein for each nucleotide (i.e GTP and GDP)

• the cellular concentration of each nucleotide

The "bottom line" is that when the overall affinity of the ras protein form nucleotides is reduced, the fraction of ras protein bound to GTP increases. As before, this results an increase in signaling and ultimately, in tumors.