Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis

Park, Min-Chul; Kang, Taehee; Jin, Da Qing; Han, Jung Min; Kim, Sang Bum; Park, Yun Jung; Cho, Kiwon; Park, Young Woo; Guo, Min; He, Weiwei; Yang, Xiang‐Lei; Schimmel, Paul; Kim, Sung Hoon

doi:10.1073/pnas.1200194109

Cited by 121 publications

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“…Interestingly, extracellular wild-type GlyRS has previously been shown to decrease ERK phosphorylation in a time-and dose-dependent fashion in the human carcinoma cell line, HCT116, functioning as a tumor-defense system (19); however, consistent with our result (Fig. 7C), this effect was not observed in the human neuroblastoma cell line, SH-SY5Y (19).…”

Section: Mutant Glyrs Aberrantly Binds the Trk Receptors And Activatesupporting

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Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Sleigh

Dawes

West

et al. 2017

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

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Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.aminoacyl-tRNA synthetase | Charcot-Marie-Tooth disease | distal spinal muscular atrophy type V | neuromuscular disease | neurodevelopment C harcot-Marie-Tooth disease (CMT) is a group of genetically diverse peripheral neuropathies that share the main pathological feature of progressive motor and sensory degeneration (1). Although lifespan is usually unaffected, patients display characteristic muscle weakness and wasting predominantly in the extremities, leading to difficulty walking, foot deformities, and reduced dexterity (2). CMT is traditionally divided into type 1/ demyelinating CMTs that display loss of peripheral nerve myelin causing reduced nerve conduction velocity (NCV), type 2/axonal CMTs typified by axon loss with relatively normal NCVs, and intermediate CMTs that share clinical features of CMT1 and -2 (1). Over 80 different genetic loci have been linked to CMT, which is known to affect ∼1/2,500 people, making it the most common group of hereditary neuromuscular disorders (3).Dominant mutations in the glycyl-tRNA synthetase (GlyRS) gene, GARS, are causative of CMT type 2D (CMT2D) [Online Mendelian Inheritance in Man (OMIM) 601472], which normally manifests during adolescence and presents with muscle weakness in the extremities (4). The 2D subtype is one of a number of CMTs associated with mutation of an aminoacyl-tRNA synthetase (ARS) gene (5-8). Humans possess 37 ARS proteins, which covalently link amino acids to their partner transfer RNAs (tRNAs), thereby charging and priming the tRNAs for protein synthesis.This housekeeping function of gl...

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Section: Mutant Glyrs Aberrantly Binds the Trk Receptors And Activatesupporting

(Expert classified)

“…neuropilin 1 (NRP1), which antagonizes VEGF signaling (18). This aberrant binding and noncell autonomous toxicity is contingent upon GlyRS secretion, which occurs from a number of different cell types in culture and is unaffected by neuropathyassociated mutations (17)(18)(19).…”

Section: Significancementioning

confidence: 99%

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Sleigh

Dawes

West

et al. 2017

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

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135

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“…The proteomic data are consistent with previous studies that demonstrated that a similar dosage of Umb had an apoptotic effect on QU-DB cells, but not on A549 cells, and only after increasing the Umb dose was cytotoxicity observed in the A549 cells (2). Notably, certain upregulated proteins observed in each cell line in the current study (GRS in the QU-DB cells and calreticulin in the A549 cells) are known to interact with immune cells in vivo and boost anti-tumor immune response (32,36,37). This may indicate that Umb has stronger in vivo anti-tumor activities compared to in vitro results.…”

Section: Discussionsupporting

confidence: 86%

“…Immune stimulatory activity of GRS indicates its therapeutic potential against tumorigenesis. GRS is a component of the translation machinery, and is secreted from macrophages in response to Fas ligand, which is released from tumor cells (32). GRS binds to various extracellular signal-regulated kinase (ERK)-activated tumor cells and releases phosphatase 2A, which in turn suppresses ERK signaling through dephosphorylation of ERK and induces apoptosis (32).…”

Section: Discussionmentioning

confidence: 99%

“…GRS is a component of the translation machinery, and is secreted from macrophages in response to Fas ligand, which is released from tumor cells (32). GRS binds to various extracellular signal-regulated kinase (ERK)-activated tumor cells and releases phosphatase 2A, which in turn suppresses ERK signaling through dephosphorylation of ERK and induces apoptosis (32). A previous study demonstrated that following in vivo administration of GRS, growth of tumors with a high level of ERK activation was strongly suppressed (32).…”

Section: Discussionmentioning

confidence: 99%

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Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

et al. 2016

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Abstract. Umbelliprenin (Umb), a natural coumarin, has demonstrated anti-tumor activities, both in vitro and particularly in vivo, in several types of cancer, including lung cancer. The present study aimed to identify molecular targets of Umb using a high-throughput approach. Lung cancer cell lines, QU-DB (large-cell lung carcinoma) and A549 (adenocarcinoma), were treated with Umb. Differentially-expressed proteins were identified using two-dimensional electrophoresis coupled to mass spectrometry. In the QU-DB cells, differential expression of proteins, including downregulation of the tumorigenic protein heat shock protein 90 kDa and upregulation of the potential anti-tumor proteins Nipsnap1 and glycine-tRNA ligase (GRS), suggested that Umb is a strong anti-tumor compound. In the A549 cells, differential expression of proteins indicated possible contradictory effects of Umbregarding tumorigenesis, which included downregulation of the tumorigenic protein cyclophilin and the tumor suppressor MST, and upregulation of stathmin (tumorigenic) and calreticulin. Calreticulun, in addition to GRS in QU-DB cells, stimulates anti-tumor immune responses in vivo. To the best of our knowledge, the present study is the first to use a high-throughput approach to identify targets of Umb in cancer. These molecular targets suggested that Umb may exhibit stronger in vitro anti-tumor activity against the large-cell carcinoma model than the adenocarcinoma model. Furthermore, it has been reported that Umb exhibits higher cytotoxicity against QU-DB cells than A549 cells in vitro, and significant Umb anti-tumor activity against lung cancer in vivo, which is consistent with previously published literature. In each cell type, immune-associated molecules were upregulated, indicating that this naturally occurring compound exhibits marked anti-tumor activity in vivo. However, further studies that investigate the effect of Umb in different in vitro models of cancer are required.

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The role of tRNA synthetases in neurological and neuromuscular disorders

2018

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Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA‐encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl‐tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear‐encoded human ARS genes have been linked to a variety of recessive and dominant tissue‐specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot–Marie–Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT‐causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).

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Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis

Cited by 121 publications

References 53 publications

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

The role of tRNA synthetases in neurological and neuromuscular disorders

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