title: Metabotropic glutamate receptor 1 mediates melanocyte transformation via transactivation of insulin-like growth factor 1 receptor.
abstract: Our laboratory previously described the oncogenic properties of metabotropic glutamate receptor 1 (mGluR1) in melanocytes. mGluR1 transformed immortalized mouse melanocytes in vitro and induced vigorous tumor formation in vivo. Subsequently, we observed the activation of PI3K/AKT in mGluR1-mediated melanocytic tumorigenesis in vivo. In particular, we identified AKT2 being the predominant isoform contributing to the activation of AKT. Suppression of Grm1 or AKT2 using an inducible Tet-R siRNA system resulted in a 60 or 30% reduction, respectively, in in vivo tumorigenesis. We show that simultaneous downregulation of Grm1 plus AKT2 results in a reduction of approximately 80% in tumor volumes, suggesting that both mGluR1 and AKT2 contribute to the tumorigenic phenotype in vivo. The discrepancy between the mild in vitro transformation characteristics and the aggressive in vivo tumorigenic phenotypes of these stable mGluR1-melanocytic clones led us to investigate the possible involvement of other growth factors. Here, we highlight a potential crosstalk network between mGluR1 and tyrosine kinase, insulin-like growth factor 1 receptor (IGF-1R).
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
authors.forename: Jessica L F
authors.initials: JL
authors.lastname: Teh
authors.forename: Raj
authors.initials: R
authors.lastname: Shah
authors.forename: Seung-Shick
authors.initials: SS
authors.lastname: Shin
authors.forename: Yu
authors.initials: Y
authors.lastname: Wen
authors.forename: Janice M
authors.initials: JM
authors.lastname: Mehnert
authors.forename: James
authors.initials: J
authors.lastname: Goydos
authors.forename: Suzie
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Grm1; IGF-1R; glutamate signaling; melanoma; transactivation