# Ras Isoforms from Lab Benches to Lives--What Are We Missing and How Far Are We?
###### Abstract  
The central protein in the oncogenic circuitry is the Ras GTPase that has been under intense scrutiny for the last four decades. From its discovery as a viral oncogene and its non-oncogenic contribution to crucial cellular functioning, an elaborate genetic, structural, and functional map of Ras is being created for its therapeutic targeting. Despite decades of research, there still exist lacunae in our understanding of Ras. The complexity of the Ras functioning is further exemplified by the fact that the three canonical Ras genes encode for four protein isoforms (H-Ras, K-Ras4A, K-Ras4B, and N-Ras). Contrary to the initial assessment that the H-, K-, and N-Ras isoforms are functionally similar, emerging data are uncovering crucial differences between them. These Ras isoforms exhibit not only cell-type and context-dependent functions but also activator and effector specificities on activation by the same receptor. Preferential localization of H-, K-, and N-Ras in different microdomains of the plasma membrane and cellular organelles like Golgi, endoplasmic reticulum, mitochondria, and endosome adds a new dimension to isoform-specific signaling and diverse functions. Herein, we review isoform-specific properties of Ras GTPase and highlight the importance of considering these towards generating effective isoform-specific therapies in the future.  
R ;  
[PERSON] et al. first hypothesized and [PERSON] et al. later experimentally proved that these oncogenes were the proto-oncogenes which, when mutated and virally transferred, were converted to transforming oncogenes [6; 7]. As observed by [PERSON] and [PERSON], the retrovirus 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 [8; 9; 10]. Later in the 1980s, [PERSON] and his colleagues found the cellular origin of this membrane-associated protein, which is dependent on guanosine-5\({}^{\prime}\)-triphosphate (GTP) binding for its activation [11; 12; 13]. 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) [14]. 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) [15]. 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).  
Figure 1: Ras is a signaling switch that regulates counteracting cellular functions like cell proliferation and apoptosis. Emerging studies have elucidated new functions of Ras e.g., in cytoskeletal rearrangement regulating cell adhesion and in parasitic infections like _Leishmania_, in addition to its well-known role in cancer progression. (Structure of Ras-April 2012, [PERSON] [5]).