title: Phosphoproteomic analysis of basal and therapy-induced adaptive signaling networks in BRAF and NRAS mutant melanoma.
abstract: Basal and kinase inhibitor driven adaptive signaling has been examined in a panel of melanoma cell lines using phosphoproteomics in conjunction with pathway analysis. A considerable divergence in the spectrum of tyrosine-phosphorylated peptides was noted at the cell line level. The unification of genotype-specific cell line data revealed the enrichment for the tyrosine-phosphorylated cytoskeletal proteins to be associated with the presence of a BRAF mutation and oncogenic NRAS to be associated with increased receptor tyrosine kinase phosphorylation. A number of proteins including cell cycle regulators (cyclin dependent kinase 1, cyclin dependent kinase 2, and cyclin dependent kinase 3), MAPK pathway components (Extracellular signal regulated kinase 1 and Extracellular signal regulated kinase 2), interferon regulators (tyrosine kinase-2), GTPase regulators (Ras-Rasb interactor 1), and controllers of protein tyrosine phosphorylation (dual specificity tyrosine (Y) phosphorylation regulated kinase 1A and protein tyrosine phosphatase receptor type A) were common to all genotypes. Treatment of a BRAF-mutant/phosphatase and tensin homologue (PTEN) null melanoma cell line with vemurafenib led to decreased phosphorylation of ERK, phospholipase C1, and β-catenin with increases in receptor tyrosine kinase phosphorylation, signal transduction and activator of signaling 3, and glycogen synthase kinase 3α noted. In NRAS-mutant melanoma, MEK inhibition led to increased phosphorylation of epidermal growth factor receptor signaling pathway components, Src family kinases, and protein kinase Cδ with decreased phosphorylation seen in STAT3 and ERK1/2. Together these data present the first systems level view of adaptive and basal phosphotyrosine signaling in BRAF- and NRAS-mutant melanoma.
authors.affiliation: The Department of Molecular Oncology, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Inna V
authors.initials: IV
authors.lastname: Fedorenko
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.forename: Ana Cecelia
authors.initials: AC
authors.lastname: Munko
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Gibney
authors.forename: John M
authors.initials: JM
authors.lastname: Koomen
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
mesh_terms: D045744:Cell Line, Tumor; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF; Biomedicine; Melanoma; NRAS; Phosphoproteomics; Signaling