title: Stimulation of oncogenic metabotropic glutamate receptor 1 in melanoma cells activates ERK1/2 via PKCepsilon.
abstract: Metabotropic glutamate receptor 1 (Grm1, formerly mGluR1) is a G protein coupled receptor (GPCR) normally expressed and functional in the central nervous system. Studies of our transgenic mouse melanoma model (TG-3) revealed that ectopic expression of Grm1 in melanocytes is sufficient to induce melanoma development in vivo [P.M. Pollock, K. Cohen-Solal, R. Sood, J. Namkoong, J.J. Martino, A. Koganti, H. Zhu, C. Robbins, I. Makalowska, S.S. Shin, Y. Marin, K.G. Roberts, L.M. Yudt, A. Chen, J. Cheng, A. Incao, H.W. Pinkett, C.L. Graham, K. Dunn, S.M. Crespo-Carbone, K.R. Mackason, K.B. Ryan, D. Sinsimer, J. Goydos, K.R. Reuhl, M. Eckhaus, P.S. Meltzer, W.J. Pavan, J.M. Trent, S. Chen, Nat. Genet. 34 (2003) 108-112.]. We have established and characterized several cell lines in vitro from independent mouse melanoma tumors [Y.E. Marín, J. Namkoong, S.S. Shin, J. Raines, K. Degenhardt, E. White, S. Chen, Neuropharmacol. 49 (2005) 70-79.]. These cell lines are useful tools in the studies of signaling events that may be mediated by Grm1 in transformed melanocytes. Here we show that stimulation of Grm1 by l-quisqualate, a group I metabotropic glutamate receptor agonist, results in inositol triphosphate (IP3) accumulation, and the activation of ERK1/2 in these cell lines. IP3 accumulation and ERK1/2 activation were inhibited by pretreatment of the tumor cells with a Grm1-specific antagonist (LY367385) or by dominant negative mutants of Grm1, demonstrating the specificity of these events. We also show that ERK1/2 activation by Grm1 was PKC-dependent, but cAMP and PKA-independent. PKCepsilon was shown to play a pivotal role in Grm1-mediated ERK1/2 phosphorylation. Insights into the signaling cascades mediated by Grm1 in melanoma cells may aid in the identification of key molecular targets for the future design of combined therapies for melanoma.
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 164 Frelinghuysen Rd., Piscataway, NJ 08854, USA.
authors.forename: Yarí E
authors.initials: YE
authors.lastname: Marín
authors.forename: Jin
authors.initials: J
authors.lastname: Namkoong
authors.forename: Karine
authors.initials: K
authors.lastname: Cohen-Solal
authors.forename: Seung-Shick
authors.initials: SS
authors.lastname: Shin
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Martino
authors.forename: Masahiro
authors.initials: M
authors.lastname: Oka
authors.forename: Suzie
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009857:Oncogenes / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016318:Quisqualic Acid / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D015544:Inositol 1,4,5-Trisphosphate; D016318:Quisqualic Acid; D000242:Cyclic AMP; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases