RasProteine

RasProteine, commonly referred to as Ras proteins, are a family of small GTPases that act as molecular switches in intracellular signaling. They relay signals from receptor tyrosine kinases to the MAPK/ERK and other pathways, thereby regulating cell proliferation, differentiation, and survival. In humans, the best known members are HRAS, KRAS and NRAS, although related Ras family proteins exist. Ras proteins cycle between an inactive GDP-bound state and an active GTP-bound state, a cycle controlled by guanine nucleotide exchange factors (GEFs) such as SOS and GTPase-activating proteins (GAPs) including NF1. In the GTP-bound form, Ras interacts with multiple effectors to propagate signals; upon GTP hydrolysis, signaling is dampened and the protein returns to the inactive state.

Structurally, Ras proteins are small (~180-190 amino acids) GTPases with conserved motifs for nucleotide binding and hydrolysis and two switch regions that determine effector interactions. They are post-translationally modified at the C-terminus and anchored to the inner surface of the plasma membrane. This membrane localization is essential for signal transmission and can involve farnesylation, palmitoylation, and, in the case of KRAS, a polybasic region.

Mutations that activate Ras signaling are common in human cancers, most frequently altering codons 12, 13, or 61 of KRAS, NRAS or HRAS. These alterations reduce GTP hydrolysis, keeping Ras in a constitutively active state and driving uncontrolled growth. Ras pathway abnormalities also contribute to developmental disorders known as Rasopathies, such as Noonan syndrome.

Therapeutic approaches have targeted Ras directly or indirectly, including inhibitors of farnesyltransferase and, more recently, compounds that lock mutant KRAS G12C in an inactive form. This is an area of active investigation. Research continues to elucidate the biology of Ras proteins and their broader role in health and disease.