Differential oncogenic potential of activated RAS isoforms in melanocytes

Abstract

RAS genes are mutated in approximately 30% of all human cancers. Interestingly, there exists a strong bias in favor of mutation of only one of the three major RAS genes in tumors of different cellular origins. NRAS mutations occur in approximately 20% of human melanomas, whereas HRAS and KRAS mutations are rare in this disease. To define the mechanism(s) responsible for this preference in melanocytes, we compared the transformation efficiencies of mutant NRAS and KRAS in immortal, non-transformed Ink4a/Arf-deficient melanocytes. NRAS mutation leads to increased cellular proliferation and is potently tumorigenic. In contrast, KRAS mutation does not enhance melanocyte proliferation and is only weakly tumorigenic on its own. Although both NRAS and KRAS activate mitogen-activated protein kinase signaling, only NRAS enhances MYC activity in these cells. Our data suggest that the activity of specific RAS isoforms is context-dependent and provide a possible explanation for the prevalence of NRAS mutations in melanoma. In addition, understanding this mechanism will have important implications for cancer therapies targeting RAS pathways.

Genetic aberrations in primary esophageal melanomas: molecular analysis of c-KIT, PDGFR, KRAS, NRAS and BRAF in a series of 10 cases

“…For mutant KRAS, the expression of a cooperating oncogene was necessary to reach a comparable transforming capacity, as mutant NRAS in a genetically welldefined system using NRAS and KRAS transformed melanocytes. 21 Thus, the simultaneous occurrence of c-Kit and a KRAS mutation may reflect such a cooperating oncogenic activity in a subset of esophageal melanomas. Interestingly, we could not confirm the results of a Japanese study, which showed a frequent occurrence of NRAS mutations in esophageal melanomas.…”

Nras in melanoma: Targeting the undruggable target

“…Furthermore, NRAS mediates activation of both MAPK and PI3K/AKT/MYC signaling. Specifically, although both NRAS and KRAS efficiently activate the classical MAPK pathway, only NRAS effectively prevents glycogen synthase kinase3 (GSK3)-mediated phosphorylation of Myc via PI3K/AKT, which results in enhanced activity of endogenous Myc protein [37]. In contrast to KRAS, NRAS and HRAS also show a more potent activation of PI3K/AKT likely due to the fact that both NRAS and HRAS colocalize to lipid rafts, whereas KRAS is excluded from lipid rafts and localizes to the disordered plasma membrane [38], resulting in a less efficient activation or a limited access to a defined subset of downstream effector proteins.…”

“…A rational explanation for the greater occurrence of NRAS mutations relies on distinct differences between the signaling capabilities of NRAS and KRAS in melanocytes [37]. When the transformation efficiencies of mutant NRAS and KRAS were compared in immortal, non-transformed Ink4a/Arf-deficient melanocytes, it was shown that in contrast to KRAS mutation, NRAS mutation leads to increased cellular proliferation and is more potently tumorigenic [37]. Furthermore, NRAS mediates activation of both MAPK and PI3K/AKT/MYC signaling.…”

Melanoma: Molecular pathogenesis and emerging target therapies (Review)

“…The aberration of NRAS often is a substitution of leucine for glutamine at residue 61, this change impairs GTP hydrolysis and maintains the protein in a state of constitutive activation (41). Mutations in other Ras isoforms are rare in melanoma, suggesting an activity context dependent on specific Ras isoforms (42).…”