In the 1960s, Jennifer Harvey observed that the viral preparation from leukemic rat induced sarcomas in newborn rats. This oncogenic viral genetic element inducing Rat Sarcoma was named H-Ras (Harvey Ras) 
. Later, while serially passing Mouse Erythroblastosis virus (MEV) in Wister-Furth (W/Fu) rats, Kirsten identified another retrovirus carrying the Ras gene 
. Initially named as a variant of Src
(sarcoma), this gene was not only mutated in a diverse spectrum of cancers but also encoded a 21k Da protein that had crucial cellular roles in normal cells.
Scolnick et al. first hypothesized and Stehelin et al. later experimentally proved that these oncogenes were the proto-oncogenes which, when mutated and virally transferred, were converted to transforming oncogenes 
. As observed by Harvey and Kirsten, the retroviruses arose as a result of the passage of the murine leukemia virus through rats. The process of genetic recombination accounts for the presence of such cellular genetic elements in simple retroviruses. A plausible hypothesis, as framed by various researchers, holds that integration of a provirus may occur upstream of a cellular sequence forming a chimera of cellular-viral genetic elements. In subsequent replications, non-homologous recombination occurs between the cellular and viral genetic elements leading to the acquisition and incorporation of cellular genetic elements into the retroviruses 
. Later in the 1980s, Scolnick and his colleagues found the cellular origin of this membrane-associated protein, which is dependent on guanosine-5′-triphosphate (GTP) binding for its activation 
. It was discovered that three loci of this gene encode for four proteins with ~80% sequence similarity: Harvey Ras (H-Ras), K-Ras A and B (Kirsten-Ras), and neuroblastoma Ras (N-Ras). K-Ras gene encodes for two proteins K-Ras4A and K-Ras4B via alternative splicing. These splice variants have distinct membrane targeting sequences. Except for a few residues, these isoforms have identical amino acid (aa) sequences in their G-domain (aa 1–86), and variations lie in the allosteric lobe (aa 87–166) and the hypervariable region (HVR) (aa 166–178/179) 
. The HVR can be further subdivided into a linker domain (aa 166–178/179) and a targeting domain, wherein the post-translationally modified residues lie (aa 179/180–189) 
. As the fourth exon in K-Ras encodes for the HVR, there lie differences in the HVR of K-Ras4A and K-Ras4B. K-Ras4A undergoes palmitoylation, whereas, K-Ras4B, which lacks a palmitoylation site, adds polylysine residues ().
Figure 2. The isoforms share sequence similarities in their G-Domain (1–165 aa). This is followed by a Hyper Variable Region (HVR) (166–188/189), which differs in all three isoforms in sequence as well as in the post-translational modifications. In addition to farnesylation, a post-translational modification that all the three isoforms undergo, H-Ras and N-Ras further undergo dual and single palmitoylation, respectively. K-Ras undergo the addition of a stretch of polylysine residues.