Suppression of G-protein–Coupled Receptor Kinase 3 Expression Is a Feature of Classical GBM That Is Required for Maximal Growth
- 1 January 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 10 (1), 156-166
- https://doi.org/10.1158/1541-7786.mcr-11-0411
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. Mol Cancer Res; 10(1); 156–66. ©2011 AACR.Other Versions
This publication has 67 references indexed in Scilit:
- β-arrestin-mediated receptor trafficking and signal transductionTrends in Pharmacological Sciences, 2011
- Molecular Mechanism of Selectivity among G Protein-Coupled Receptor Kinase 2 InhibitorsMolecular Pharmacology, 2011
- The complex G protein‐coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targetsBritish Journal of Pharmacology, 2010
- Site-specific Phosphorylation of CXCR4 Is Dynamically Regulated by Multiple Kinases and Results in Differential Modulation of CXCR4 SignalingPublished by Elsevier BV ,2010
- Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1Cancer Cell, 2010
- G protein–coupled receptor kinase 2 (GRK2) modulation and cell cycle progressionProceedings of the National Academy of Sciences of the United States of America, 2009
- Chemokine signaling in cancer: One hump or two?Seminars in Cancer Biology, 2009
- Decreased GRK3 but not GRK2 expression in frontal cortex from bipolar disorder patientsInternational Journal of Neuropsychopharmacology, 2009
- A polymorphism of G-protein coupled receptor kinase5 alters agonist-promoted desensitization of β2-adrenergic receptorsPharmacogenetics and Genomics, 2008
- Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2The EMBO Journal, 2006