Somatic Mutations in GRM1 in Cancer Alter Metabotropic Glutamate Receptor 1 Intracellular Localization and Signaling

Abstract

The activity of metabotropic glutamate receptors (mGluRs) is known to be altered as the consequence of neurodegenerative diseases such as Alzheimer, Parkinson, and Huntington disease. However, little attention has been paid to this receptor family's potential link with cancer. Recent reports indicate altered mGluR signaling in various tumor types, and several somatic mutations in mGluR1a in lung cancer were recently described. Group 1 mGluRs (mGluR1a and mGluR5) are coupled primarily to Gaq, leading to the activation of phospholipase C and to the formation of diacylglycerol and inositol 1,4,5-trisphosphate, leading to the release of Ca 21 from intracellular stores and protein kinase C (PKC) activation. In the present study, we investigated the intracellular localization and G protein-dependent and -independent signaling of eight GRM1 (mGluR1a) somatic mutations. Two mutants found in close proximity to the glutamate binding domain and cysteine-rich region (R375G and G396V) show both decreased cell surface expression and basal inositol phosphate (IP) formation. However, R375G shows increased ERK1/2 activation in response to quisqualate stimulation. A mutant located directly in the glutamate binding site (A168V) shows increased quisqualate-induced IP formation and, similar to R375G, increased ERK1/2 activation. Additionally, a mutation in the G protein-coupled receptor kinase 2/PKC regulatory region (R696W) shows decreased ERK1/2 activation, whereas a mutation within the Homer binding region in the carboxylterminal tail (P1148L) does not alter the intracellular localization of the receptor, but it induces changes in cellular morphology and exhibits reduced ERK1/2 activation. Taken together, these results suggest that mGluR1a signaling in cancer is disrupted by somatic mutations with multiple downstream consequences.

Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing

“…Although mutations of TP53 and APC were not detected in all cells in the major clone, this could be caused by the failure to cover these two genes during sequencing. A high proportion of these cells also contained somatic mutations in other cancer-related genes, such as, GRM1 and RELN whose genetic alterations have been reported in other human tumors [16,17]. In contrast, the minor tumor cell subset predominantly contained CDC27 and PABPC1 mutations (Figure 3).…”

Role of Spinophilin in Group I Metabotropic Glutamate Receptor Endocytosis, Signaling, and Synaptic Plasticity

“…We assessed IP formation using wild-type FLAG-mGluR1a and FLAG-mGluR1b constructs as well as a mutant FLAG-mGluR5a cDNA construct that has a single amino acid mutation (A154V) in the glutamate binding region. This residue was analogous to Ala-168 in mGluR1a, which when mutated to valine causes low basal IP formation so that agonist-stimulated responses could be measured (36). Agonist stimulation of either FLAG-mGluR1a, FLAGmGluR1b, or FLAG-mGluR5a-A154V resulted in a dose-dependent increase in IP formation over 30 min that was not altered by the expression of GFP-spinophilin (Fig.…”

DOTS-Finder: a comprehensive tool for assessing driver genes in cancer genomes

“…At the top of the list of predicted OGs is EGFR , consistent with the fact that EGFR is a key oncogenic player in never smokers with LUAD. Besides the identification of very well-known cancer genes such as SMAD4 , STK11 , SETD2 , MET , KEAP1 , TP53 and KRAS , we also identified several putative driver genes that might have relevant cancer development functions: somatic mutations in GRM1 disrupt signaling with multiple downstream consequences [50]; mutations in RPL5 have been recently described as a potential oncogenic factor in T-cell acute lymphoblastic leukemia [51]; inactivating mutations in the SHA gene, which has a role as a TSG, have been identified in familial paragangliomas [52,53]; WRN encodes a helicase that is important for genomic integrity and involved in the repair of double strand DNA breaks and defects in this gene are the cause of the aging-promoting Werner syndrome and copy number variations or epigenetic inactivation of it have been recently found in never smokers with LUAD [54] and non-small cell lung cancer [55], respectively.…”