title: A New View of Ras Isoforms in Cancers.
abstract: Does small GTPase K-Ras4A have a single state or two states, one resembling K-Ras4B and the other N-Ras? A recent study of K-Ras4A made the remarkable observation that even in the absence of the palmitoyl, K-Ras4A can be active at the plasma membrane. Importantly, this suggests that K-Ras4A may exist in two distinct signaling states. In state 1, K-Ras4A is only farnesylated, like K-Ras4B; in state 2, farnesylated and palmitoylated, like N-Ras. The K-Ras4A hypervariable region sequence is positively charged, in between K-Ras4B and N-Ras. Taken together, this raises the possibility that the farnesylated but nonpalmitoylated state 1, like K-Ras4B, binds calmodulin and is associated with colorectal and other adenocarcinomas like lung cancer and pancreatic ductal adenocarcinoma. On the other hand, state 2 may be associated with melanoma and other cancers where N-Ras is a major contributor, such as acute myeloid leukemia. Importantly, H-Ras has two, singly and doubly, palmitoylated states that may also serve distinct functional roles. The multiple signaling states of palmitoylated Ras isoforms question the completeness of small GTPase Ras isoform statistics in different cancer types and call for reevaluation of concepts and protocols. They may also call for reconsideration of oncogenic Ras therapeutics.
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. NussinoR@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland.
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Tsai
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland. Department of Biotechnology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Mayukh
authors.initials: M
authors.lastname: Chakrabarti
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
mesh_terms: D000818:Animals; D011905:Genes, ras; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D018631:ras Proteins