The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling

Likhite, Neah; Jackson, Christopher; Liang, Mao‐Shih; Krzyzanowski, Michelle; Lei, Pedro; Wood, John J.; Birkaya, Barbara; Michaels, Kerry; Andreadis, Stelios T.; Clark, Stewart D.; Yu, Michael C.; Ferkey, Denise M.

doi:10.1126/scisignal.aad0872

Cited by 17 publications

(28 citation statements)

References 54 publications

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“…Protein arginine methyltransferase 5 (PRMT5) has been shown to interact directly with and effect the methylation of the dopamine D2 receptor (D2R). This would therefore represent a potential new signaling pathway with which novel pharmacological agents could modulate GPCR signaling by changing the methylation status of key cell signaling associated with DDR responses [ 168 ]. In addition to this link between D2Rs and pro-aging mechanisms, therapeutic targeting of D2R-associated DNA damage effects may also yield the creation of novel anti-neoplastic agents [ 169 ].…”

Section: G Protein-coupled Receptor Systems: Intersections With Dnmentioning

confidence: 99%

G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes

Leysen

Gastel

Hendrickx

et al. 2018

IJMS

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G protein-coupled receptors (GPCRs) and their associated proteins represent one of the most diverse cellular signaling systems involved in both physiological and pathophysiological processes. Aging represents perhaps the most complex biological process in humans and involves a progressive degradation of systemic integrity and physiological resilience. This is in part mediated by age-related aberrations in energy metabolism, mitochondrial function, protein folding and sorting, inflammatory activity and genomic stability. Indeed, an increased rate of unrepaired DNA damage is considered to be one of the ‘hallmarks’ of aging. Over the last two decades our appreciation of the complexity of GPCR signaling systems has expanded their functional signaling repertoire. One such example of this is the incipient role of GPCRs and GPCR-interacting proteins in DNA damage and repair mechanisms. Emerging data now suggest that GPCRs could function as stress sensors for intracellular damage, e.g., oxidative stress. Given this role of GPCRs in the DNA damage response process, coupled to the effective history of drug targeting of these receptors, this suggests that one important future activity of GPCR therapeutics is the rational control of DNA damage repair systems.

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Section: G Protein-coupled Receptor Systems: Intersections With Dnmentioning

confidence: 99%

G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes

Leysen

Gastel

Hendrickx

et al. 2018

IJMS

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“…Although a large-scale proteomics analysis performed in 2003 identified several GPCRs as substrates of an anti-methylarginine antibody ( Boisvert et al 2003 ), there was no direct evidence at that time that this receptor class is regulated by methylation. In 2015, we reported the first functional evidence that protein arginine methylation regulates GPCR signaling ( Likhite et al 2015 ) . Methylation of D2-like dopamine receptors (human D2 and C. elegans DOP-3 ) by protein arginine methyltransferase 5 (human PRMT5 and C .…”

mentioning

confidence: 99%

“…Methylation of D2-like dopamine receptors (human D2 and C. elegans DOP-3 ) by protein arginine methyltransferase 5 (human PRMT5 and C . elegans PRMT-5 , respectively) promoted signaling in both cell culture and in vivo ( Likhite et al 2015 ). The D2-like dopamine receptor family was identified as a possible substrate for PRMT5 in a bioinformatics analysis that examined GPCRs for predicted methylation motifs (RGG or RXR) in their intracellular domains.…”

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confidence: 99%

“…The third intracellular loop of both the human D2 and C. elegans DOP-3 receptors was methylated by human PRMT5 in vitro , and changing the conserved arginines of the putative methylation motif to alanines diminished receptor methylation. Correspondingly, changing these arginines to disrupt the methylation motif also diminished signaling through both of these receptors ( Likhite et al 2015 ). Combined, the results of that study revealed that arginine methylation promotes signaling through the D2 receptor to dampen cAMP signaling in cultured human cells, and also promotes DOP-3 signaling to regulate C. elegans behavior.…”

mentioning

confidence: 99%

“…PRMT5 has been shown to influence gene expression, snRNP biogenesis, the DNA damage response, and germ cell development ( Meister et al 2001 ; Fabbrizio et al 2002 ; Ancelin et al 2006 ; Tee et al 2010 ; He et al 2011 ; Huang et al 2011 ). In their study of D2-like dopamine receptors, Likhite et al (2015) added to the growing list of PRMT5 substrates and described the founding members of a new class of proteins – GPCRs – that are functionally regulated by arginine methylation.…”

mentioning

confidence: 99%

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The Protein Arginine Methyltransferase PRMT-5 Regulates SER-2 Tyramine Receptor-Mediated Behaviors inCaenorhabditis elegans

Bowitch

Michaels

et al. 2018

G3 Genes|Genomes|Genetics

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G protein-coupled receptors are 7-pass transmembrane receptors that couple to heterotrimeric G proteins to mediate cellular responses to a diverse array of stimuli. Understanding the mechanisms that regulate G protein-coupled receptors is crucial to manipulating their signaling for therapeutic benefit. One key regulatory mechanism that contributes to the functional diversity of many signaling proteins is post-translational modification. Whereas phosphorylation remains the best studied of such modifications, arginine methylation by protein arginine methyltransferases is emerging as a key regulator of protein function. We previously published the first functional evidence that arginine methylation of G protein-coupled receptors modulates their signaling. We report here a third receptor that is regulated by arginine methylation, the Caenorhabditis elegans SER-2 tyramine receptor. We show that arginines within a putative methylation motif in the third intracellular loop of SER-2 are methylated by PRMT5 in vitro. Our data also suggest that this modification enhances SER-2 signaling in vivo to modulate animal behavior. The identification of a third G protein-coupled receptor to be functionally regulated by arginine methylation suggests that this post-translational modification may be utilized to regulate signaling through a broad array of G protein-coupled receptors.

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The Structure and Function of the PRMT5:MEP50 Complex

Antonysamy

2017

Subcellular Biochemistry

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Protein arginine methyltransferase 5 (PRMT5) plays multiple roles in cellular processes at different stages of the cell cycle in a tissue specific manner. PRMT5 in complex with MEP50/p44/WDR77 associates with a plethora of partner proteins to symmetrically dimethylate arginine residues on target proteins in both the nucleus and the cytoplasm. Overexpression of PRMT5 has been observed in several cancers, making it an attractive drug target. The structure of the 453 kDa heterooctameric PRMT5:MEP50 complex bound to an S-adenosylmethionine analog and a substrate peptide provides valuable insights into this intriguing target.

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The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling

Cited by 17 publications

References 54 publications

G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes

G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes

The Protein Arginine Methyltransferase PRMT-5 Regulates SER-2 Tyramine Receptor-Mediated Behaviors inCaenorhabditis elegans

The Structure and Function of the PRMT5:MEP50 Complex

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