Ras GTPase is a family of proteins found in all animal cells and organs. These proteins act as fundamental communicators, transmitting signals from outside the cell to its interior. They influence a wide array of basic biological processes and are a prototypical member of the Ras superfamily.
How Ras Works as a Molecular Switch
Ras proteins function as molecular switches, cycling between an “on” (active) and an “off” (inactive) state. In its inactive form, Ras is bound to guanosine diphosphate (GDP). To become active, guanine nucleotide exchange factors (GEFs) facilitate the exchange of GDP for guanosine triphosphate (GTP). This GTP-bound state represents the “on” conformation.
The return to the inactive state occurs through the hydrolysis of GTP back to GDP. While Ras has an intrinsic ability to break down GTP, this activity is too slow for efficient cellular signaling. GTPase-activating proteins (GAPs) bind to Ras and accelerate this GTP hydrolysis, returning Ras to its inactive, GDP-bound state. This on-off switching mechanism allows Ras to control intracellular signaling networks.
Its Role in Cellular Processes
Ras proteins relay signals from the cell’s exterior to its nucleus, influencing various normal cellular activities. When activated, Ras initiates signaling cascades that influence fundamental biological processes. These include cell growth (increase in cell size) and cell proliferation (cell division).
Ras also contributes to cell differentiation (where a less specialized cell becomes a more specialized type) and cell survival. One well-studied pathway activated by Ras is the mitogen-activated protein (MAP) kinase cascade, which ultimately leads to the transcription of genes that control these cellular functions. Another pathway, the PI3K/AKT/mTOR pathway, stimulated by Ras, impacts protein synthesis, cell migration, growth, and the inhibition of programmed cell death.
Ras and Disease Development
Mutations in Ras genes are frequently linked to various human diseases, with cancer being a prominent example. These mutations can lock the Ras protein in its “on” (active) state, preventing it from switching off. This continuous activation leads to uncontrolled cell growth and division, a hallmark of cancer.
Ras mutations are among the most common genetic alterations in human cancers, found in approximately 20% to 25% of all human tumors. In certain cancer types, the prevalence is significantly higher; for instance, Ras mutations are found in nearly all pancreatic cancers, about half of colorectal cancers, and approximately one-third of lung cancers. These mutations often occur at specific “hotspot” residues like G12, G13, and Q61, which disrupt the protein’s ability to hydrolyze GTP. The persistent activation of Ras due to these mutations drives continuous signaling through pathways like MAPK and PI3K/AKT/mTOR, giving cancer cells a significant advantage in growth, survival, and potential to spread.