Protein arginine methyltransferases (PRMTs) as therapeutic targets

Cha, Boksik; Jho, Eek‐hoon

doi:10.1517/14728222.2012.688030

Cited by 49 publications

(36 citation statements)

References 107 publications

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“…In contrast, myotonic dystrophy type I (DM1) patients display greater type 1 myofiber atrophy in comparison to type 2 muscle fibers (9). In addition, muscle disuse due to bed rest and spinal cord injury has been reported to cause more pronounced muscle wasting in type 1 fibers relative to type 2 (11,12). It remains obscure as to why certain fiber types are preferentially affected in these, and other conditions.…”

Section: Introduction To Skeletal Musclementioning

confidence: 99%

“…PRMT1 and PRMT4 (also known as co-activator-associated arginine methyltransferase 1; CARM1) are type I PRMTs, which form asymmetric dimethylarginines (ADMA) by transferring two monomethyl groups from S-adenosyl-L-methionine to the same nitrogen atom of arginine residues on target proteins (10,11). PRMT5 is a type II PRMT that generates symmetric dimethylarginine (SDMA) marks on target substrates (10,11). PRMT1, CARM1, and PRMT5 account for over 90% of cellular methyltransferase activity (12).…”

Section: Introductionmentioning

confidence: 99%

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Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

Stouth

Manta

Ljubicic

2018

American Journal of Physiology-Cell Physiology

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Lay AbstractSkeletal muscle is a plastic tissue that is capable of adapting to various physiological demands. Previous work suggests that protein arginine methyltransferases (PRMTs) are important players in the regulation of skeletal muscle remodelling. However, their role in disuse-induced muscle plasticity is unknown. Therefore, the purpose of this study was to investigate the role of PRMTs within the context of early, upstream signaling pathways that mediate disuse-evoked muscle remodelling. We found differential responses of the PRMTs to muscle denervation, suggesting a unique sensitivity to, or regulation by, potential upstream signaling pathways. AMP-activated protein kinase (AMPK) was among the molecules that experienced a rapid change in activity following disuse. These alterations in AMPK predicted many of the modifications in PRMT biology during inactivity, suggesting that PRMTs factor into the molecular mechanisms that precede neurogenic muscle atrophy. This study expands our understanding of the role of PRMTs in regulating skeletal muscle plasticity.

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Section: Introduction To Skeletal Musclementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

Stouth

Manta

Ljubicic

2018

American Journal of Physiology-Cell Physiology

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“…During arginine methylation, PRMTs transfer methyl groups from S-adenosylmethionine (SAM) to the guanidine nitrogen of specific arginine residues on their target proteins, which in turn alter the protein structure, protein-protein interaction, protein localization, and enzyme activity that are critical for various cellular functions (10). For example, signal transduction, RNA processing, DNA repair, and gene transcription are regulated by arginine methylation (3,11,12).…”

Section: Introductionmentioning

confidence: 99%

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

Liao

Hsu

Xia

et al. 2015

Journal of Clinical Investigation

118

121

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R e s e a R c h a R t i c l e4 5 3 0 jci.org Volume 125 Number 12 December 2015 ing activation of HER2 or MET signaling, mutation of PIK3CA and BRAF, or expression status of PTEN, but retrospective analyses revealed inconsistent and controversial findings (16). So far, the most accepted predictive marker for poor cetuximab response is mutant KRAS status, due to its association with poor survival rate under cetuximab treatment in colorectal cancer clinical trials (17)(18)(19)(20). Therefore, American Society of Clinical Oncology recommended cetuximab treatment for only patients with WT KRAS (21). However, there is increasing evidence showing that WT KRAS is not sufficient to confer sensitivity to cetuximab (22)(23)(24), and some patients with mutant KRAS are still sensitive to cetuximab (16,(25)(26)(27)(28). These findings suggest that further investigation into the underlying mechanisms of cetuximab resistance and identification of a better predictor for cetuximab response are ing of chemotherapeutic agents have improved the response and survival rate of colorectal patients. Currently, rational targeting of molecular signaling pathways that are involved in the etiology of malignancies is one of the most promising strategies in novel anticancer drug development (13). Owing to the role of EGFR in tumorigenesis, new classes of drugs that target EGFR are among the most clinically advanced molecular-targeted therapies. Although EGFR tyrosine kinase inhibitors combined with chemotherapy presented severe toxicity and limited effect (14), the combination of EGFR monoclonal antibody, such as cetuximab and panitumumab, with chemotherapy has shown efficacy in colorectal cancer treatment (15). Unfortunately, resistance to EGFR-targeted therapy has recently been observed. Many mechanisms have been proposed to explain the poor response to cetuximab, includ-

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“…Conversely, dysregulated PRMT activity is known to be linked to a variety of cancers and other diseases (3,4). Coactivator associated arginine methyltransferase 1 (CARM1, also known as PRMT4) is directly involved in numerous cellular processes via methylation of the histone H3 tail peptide, splicing factors, RNA binding proteins, and coactivation of nuclear receptors (1,5).…”

mentioning

confidence: 99%

“…Although the different PRMTs vary significantly in overall size and sequence, they share a common active site architecture defined by specific amino acids (belonging to the so-called motifs I to IV) known to be key for catalysis (Fig. 1A) (1)(2)(3)(4)12). Most notable in this regard are residues involved in hydrogen bonding to the adenosine moiety of AdoMet and two conserved glutamate residues that form the so-called "double-E loop" critical for chelating and orienting the guanidine group of the target arginine residue.…”

mentioning

confidence: 99%

Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1

Haren

Marechal

Troffer-Charlier

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Coactivator associated arginine methyltransferase 1 (CARM1) is a member of the protein arginine methyltransferase (PRMT) family and methylates a range of proteins in eukaryotic cells. Overexpression of CARM1 is implicated in a number of cancers, and it is therefore seen as a potential therapeutic target. Peptide sequences derived from the well-defined CARM1 substrate poly(A)-binding protein 1 (PABP1) were covalently linked to an adenosine moiety as in the AdoMet cofactor to generate transition state mimics. These constructs were found to be potent CARM1 inhibitors and also formed stable complexes with the enzyme. High-resolution crystal structures of CARM1 in complex with these compounds confirm a mode of binding that is indeed reflective of the transition state at the CARM1 active site. Given the transient nature of PRMT–substrate complexes, such transition state mimics represent valuable chemical tools for structural studies aimed at deciphering the regulation of arginine methylation mediated by the family of arginine methyltransferases

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Protein arginine methyltransferases (PRMTs) as therapeutic targets

Cited by 49 publications

References 107 publications

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response

Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1

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