Dataset Information

Protein arginine methyltransferase 5 (PRMT5) signaling suppresses protein kinase C?- and p38?-dependent signaling and keratinocyte differentiation.

ABSTRACT: PKC? is a key regulator of keratinocyte differentiation that activates p38? phosphorylation leading to increased differentiation as measured by an increased expression of the structural protein involucrin. Our previous studies suggest that p38? exists in association with protein partners. A major goal is to identify these partners and understand their role in regulating keratinocyte differentiation. In this study we use affinity purification and mass spectrometry to identify protein arginine methyltransferase 5 (PRMT5) as part of the p38? signaling complex. PRMT5 is an arginine methyltransferase that symmetrically dimethylates arginine residues on target proteins to alter target protein function. We show that PRMT5 knockdown is associated with increased p38? phosphorylation, suggesting that PRMT5 impacts the p38? signaling complex. At a functional level we show that PRMT5 inhibits the PKC?- or 12-O-tetradecanoylphorbol-13-acetate-dependent increase in human involucrin expression, and PRMT5 dimethylates proteins in the p38? complex. Moreover, PKC? expression reduces the PRMT5 level, suggesting that PKC? activates differentiation in part by reducing PRMT5 level. These studies indicate antagonism between the PKC? and PRMT5 signaling in control of keratinocyte differentiation.

SUBMITTER: Kanade SR

PROVIDER: S-EPMC3293539 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Protein arginine methyltransferase 5 (PRMT5) signaling suppresses protein kinase Cδ- and p38δ-dependent signaling and keratinocyte differentiation.

Kanade Santosh R SR Eckert Richard L RL

The Journal of biological chemistry 20111223 10

PKCδ is a key regulator of keratinocyte differentiation that activates p38δ phosphorylation leading to increased differentiation as measured by an increased expression of the structural protein involucrin. Our previous studies suggest that p38δ exists in association with protein partners. A major goal is to identify these partners and understand their role in regulating keratinocyte differentiation. In this study we use affinity purification and mass spectrometry to identify protein arginine met ...[more]

PMID: 22199349

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Project description:Protein arginine methylation is emerging as a pivotal posttranslational modification involved in regulating various cellular processes; however, its role in erythropoiesis is still elusive. Erythropoiesis generates circulating red blood cells which are vital for body activity. Deficiency in erythroid differentiation causes anemia which compromises the quality of life. Despite extensive studies, the molecular events regulating erythropoiesis are not fully understood. This study showed that the increase in protein arginine methyltransferase 1 (PRMT1) levels, via transfection or protein transduction, significantly promoted erythroid differentiation in the bipotent human K562 cell line as well as in human primary hematopoietic progenitor CD34(+) cells. PRMT1 expression enhanced the production of hemoglobin and the erythroid surface marker glycophorin A, and also up-regulated several key transcription factors, GATA1, NF-E2 and EKLF, which are critical for lineage-specific differentiation. The shRNA-mediated knockdown of PRMT1 suppressed erythroid differentiation. The methyltransferase activity-deficient PRMT1G80R mutant failed to stimulate differentiation, indicating the requirement of arginine methylation of target proteins. Our results further showed that a specific isoform of p38 MAPK, p38?, promoted erythroid differentiation, whereas p38? did not play a role. The stimulation of erythroid differentiation by PRMT1 was diminished in p38?- but not p38?-knockdown cells. PRMT1 appeared to act upstream of p38?, since expression of p38? still promoted erythroid differentiation in PRMT1-knockdown cells, and expression of PRMT1 enhanced the activation of p38 MAPK. Importantly, we showed for the first time that PRMT1 was associated with p38? in cells by co-immunoprecipitation and that PRMT1 directly methylated p38? in in vitro methylation assays. Taken together, our findings unveil a link between PRMT1 and p38? in regulating the erythroid differentiation program and provide evidence suggesting a novel regulatory mechanism for p38? through arginine methylation.

Dataset Information

Protein arginine methyltransferase 5 (PRMT5) signaling suppresses protein kinase C?- and p38?-dependent signaling and keratinocyte differentiation.

Publications

Protein arginine methyltransferase 5 (PRMT5) signaling suppresses protein kinase Cδ- and p38δ-dependent signaling and keratinocyte differentiation.

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