title: Suppression of G-protein-coupled receptor kinase 3 expression is a feature of classical GBM that is required for maximal growth.
abstract: G-protein-coupled receptor kinases (GRK) regulate the function of G-protein-coupled receptors (GPCR). Previously, we found that GPCR (CXCR4)-mediated astrocytoma growth was dependent upon abnormally sustained CXCR4 signaling and was correlated with decreased GRK-mediated receptor phosphorylation. As CXCR4 has also been implicated in the stimulation of high-grade glioma growth, we sought to determine whether dysregulation of GRK expression and/or function might also be present in high-grade gliomas. In an analysis of data from The Cancer Genome Atlas, we found that GRK3 expression is frequently decreased in glioblastoma (GBM) of the classical subtype, which possesses signature amplification or mutational activation of the epidermal growth factor (EGF) receptor. We tested the correlation between GRK3 expression and GBM subtypes, as well as the relationship between the activation of the EGF and other growth factor receptor pathways and GRK expression. In analyses of primary GBM tissue and RNA specimens, we found that GRK3 expression is correlated with established criteria for GBM subtyping including expression of EGF receptor, platelet-derived growth factor receptor (PDGFR)α, NF1, PTEN, CDKN2A, and neurofilament. We also found that established drivers of gliomagenesis, the EGF, PDGF, and TGF-β pathways, all regulate GRK expression. Coculture experiments, designed to mimic critical interactions between tumor and brain microvascular endothelial cells, showed that specifically increasing GRK3 expression reduced the trophic effect of endothelial cells on tumor cells. Together, these experiments show that GRK3 is a negative regulator of cell growth whose expression is preferentially reduced in GBM of the classical subtype as a consequence of activity in primary gliomagenic pathways.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Woerner
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.forename: Kristin R
authors.initials: KR
authors.lastname: Brown
authors.forename: Erin
authors.initials: E
authors.lastname: Jackson
authors.forename: Sonika M
authors.initials: SM
authors.lastname: Dahiya
authors.forename: Paul
authors.initials: P
authors.lastname: Mischel
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Benovic
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human
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