HRAS Research Reagents

HRAS Background

The Harvey rat sarcoma viral proto-oncogene homolog (HRAS), the first identified human proto-oncogene ^[1], is one of the RAS oncogene family related to the transforming genes of mammalian sarcoma retroviruses ^[2][3]. The product of this gene HRAS protein mediates many intracellular signaling pathways involved in controlling cell growth, differentiation, and apoptosis. HRAS undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. As a GTPase, HRAS is active in the GTP bound state and inactive in the GDP bound state, just like a switch ^[4]. The switching between the two is regulated by guanine nucleotide exchange factors (GEF) ^[5]. HRAS is activated through the epidermal growth factor (EGF) receptor tyrosine kinase (RTK). The RTK recruits a GEF protein known as Son-of-sevenless (SOS) that promotes the GTP-bound state allowing activation of Ras via RTK. The activation of HRAS leads to further downstream direct activation of Raf serine/threonine kinase (activated via phosphorylation) ^[6]. Activated Raf subsequently turns on MEK1/2 protein kinase and then results in activation of ERK1/2 that leads to intranuclear activation of transcription factors. This process is the Ras/Raf/MEK/ERK cascade pathway, which plays a variety of roles in cell cycle regulation, apoptosis, and cell differentiation ^[7]. Somatic mutations in HRAS are present in many cancers, and the vast majority of mutations affect codons 12 and 13, leading to a constitutively active protein. Germline mutations in HRAS cause Costello syndrome (CS), which is a congenital disease characterized by postnatal growth retardation, short stature, tumor predisposition, developmental delay, and abnormalities of the heart (cardiomyopathy), skin and skeletal muscles ^[8]. Besides, the expression of activated H-Ras was shown to be sufficient to promote cardiomyocyte hypertrophy ^[9-11]. Sheng H et al. delineated an important role for PI3K/Akt in HRas-mediated transformation of intestinal epithelial cells ^[12].

[1] Parada LF, Tabin CJ, et al. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene [J]. Nature 1982, 297: 474–478.
[2] Wong-Staal F, Dalla-Favera R, et al. Three distinct genes in human DNA related to the transforming genes of mammalian sarcoma retroviruses [J]. Science. 1981, 213 (4504): 226–8.
[3] Russell MW, Munroe DJ, et al. A 500-kb physical map and contig from the Harvey ras-1 gene to the 11p telomere (PDF) [J]. Genomics. 1986, 35 (2): 353–60.
[4] Vetter, I.R., and Wittinghofer, A. The guanine nucleotide-binding switch in three dimensions. Science 294, 2001, 1299–1304.
[5] D. Esser, B. Bauer, et al. Structure determination of the ras-binding domain of the Ral-specific guanine nucleotide exchange factor Rlf [J]. Biochemistry, 1998, vol. 37, no. 39, pp. 13453–13462.
[6] Drosten, M., Dhawahir, A., et al. Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J. 2010, 29, 1091–1104.
[7] Steelman LS, Pohnert SC, et al. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis [J]. Leukemia. 2004 Feb; 18(2):189-218.
[8] Gripp KW, Lin AE, et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation [J]. Am J Med Genet 2006, 140A: 1–7.
[9] Thorburn A, Thorburn J, et al. HRas-dependent pathways can activate morphological and genetic markers of cardiac muscle cell hypertrophy [J]. J Biol Chem. 1993; 268:2244–2249.
[10] Ramirez MT, Sah VP, et al. The MEKK-JNK pathway is stimulated by alpha1-adrenergic receptor and ras activation and is associated with in vitro and in vivo cardiac hypertrophy [J]. J Biol Chem. 1997; 272:14057–14061.
[11] LaMorte VJ, Thorburn J, et al. Gq- and ras-dependent pathways mediate hypertrophy of neonatal rat ventricular myocytes following alpha 1-adrenergic stimulation [J]. J Biol Chem. 1994; 269:13490–13496.
[12] Sheng H, Shao J, et al. Akt/PKB activity is required for Ha-Ras-mediated transformation of intestinal epithelial cells [J]. J Biol Chem. 2001 Apr 27;276(17):14498-504.