Ras proteins

RAS proteins (RAS of: rat sarcoma forming viruses - oncogenes). The RAS proteins are membrane-associated enzymes which, as GTP-binding proteins (G-proteins), perform an important control function in cellular signal transduction.

The RAS gene encoding the RAS proteins is located on chromosomes 12p (KRAS), 11p (HRAS) and 1p13.2 (NRAS). It contains the blueprint for the homologous and structurally related p21 proteins. RAS proteins are called "K-RAS, N-RAS and H-RAS" like the gene of the same name. The mammalian RAS proteins consist of 188 or 189 amino acids (Mr 21kDa); they are also referred to as p21 proteins, shortened to p21 or simply RAS.

RAS proteins support the signal transduction from receptor tyrosine kinases to the cell nucleus, thereby triggering cell growth or differentiation.

The mammalian cells contain 3 very similar RAS genes (HRAS, KRAS,NRAS). The RAS protein (p21), subsequently representative of the product of all three genes, occurs in all cells. p21 is synthesized in the cytosol and is subjected to a series of post-translational modifications (farnesylation, prenylation; proteolytic cleavage of the three C-terminal amino acids; methyl esterification of the new C-terminal cysteine residue; acylation with palmitic acid). The modified p21 is located in the inner cell membrane.

Esterification with palmitic acid (palmitoylation) increases the affinity of RAS proteins to the cell membrane. After localisation in the cell membrane, the RAS proteins bind GTP and GDP and possess intrinsic GTPase activity. RAS proteins are therefore enzymes that cleave a phosphate molecule from GTP (guanosine triphosphate).

RAS proteins are active with bound GTP (GTP-RAS). They are inactive if they are bound to GDP (GDP-RAS).

Normally, RAS are present in the inactive, GDP-bound form. It is converted into the active GTP-bound form by growth signal triggers. RAS can only interact with other signaling proteins (e.g. RAF kinases) in the GTP-bound state, which in turn mediate signal transduction.

Activating RAS gene mutations lead to uncontrolled cell growth and play an important role in malignant transformations. Through this mutation, the RAS protein loses its GTPase activity. The change from the GTP-RAS form to the GDP-RAS form is blocked. This leads to an accumulation of active RAS (GTP-RAS) and hence to a permanent growth-stimulating signal in the cell. Mutations in the RAS gene thus cause the cell to be ready for malignant transformation.