Activation of Pre-mRNA Splicing by Human RNPS1 Is Regulated by CK2 Phosphorylation

Trembley, Janeen H.; Tatsumi, Sawako; Sakashita, Eiji; Loyer, Pascal; Slaughter, Clive A.; Suzuki, Hitoshi; Endo, Hitoshi; Kidd, Vincent J.; Mayeda, Akila

doi:10.1128/mcb.25.4.1446-1457.2005

Cited by 50 publications

(61 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, it is phosphorylated at serine 53 (Trembley et al, 2005) by CK2 at least in vitro. This phosphorylation stimulated the splicing activity of RNPS1.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protein kinase CK2 interacts with the splicing factor hPrp3p

et al. 2007

View full text Add to dashboard Cite

Numerous signalling pathways in cells are influenced by the ubiquitous Ser/Thr protein kinase CK2. Protein kinase CK2 is composed of two regulatory b-subunits and two catalytic a-or a 0 -subunits. Several of the known CK2 substrates are proteins known to regulate transcriptional events. Here, we describe that protein kinase CK2 interacts with the splicing factor hPrp3p, which is important for the assembly of the spliceosome. In a twohybrid screen hPrp3p is exclusively bound to the catalytic a-or a 0 -subunits of CK2 but not to the regulatory bsubunit. The interaction was confirmed by coimmunoprecipitation experiments in vitro and in vivo. Moreover, both proteins colocalized in nuclear speckles which is typical for splicing factor compartments within the nucleus. Phosphorylation experiments revealed that hPrp3p is also a substrate of protein kinase CK2. The main phosphorylation site was mapped to C-terminal residues. In vitro and in vivo splicing assays showed that the splicing activity is significantly influenced by the CK2-hPrp3p interaction. Thus, these data showed that CK2 is involved in the regulation of RNA processing.

show abstract

“…Furthermore, it is phosphorylated at serine 53 (Trembley et al, 2005) by CK2 at least in vitro. This phosphorylation stimulated the splicing activity of RNPS1.…”

Section: Discussionmentioning

confidence: 99%

“…The phosphorylation of the CTD is necessary for the switch of the initiation to the elongation step of transcription. CK2 is also directly involved in the splicing process as it phosphorylates RNPS1, which is a splicing regulator whose activator function is, at least in part, controlled by CK2 phosphorylation (Trembley et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Protein kinase CK2 interacts with the splicing factor hPrp3p

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Antibodies-The CDK11 antibodies P2N100 and P1C have been described previously (12,24). The cyclin L antibodies were produced by immunization of rabbits with purified His 6 -tagged full-length cyclin L1␤ (pan-L antibody), His 6 -tagged cyclin L1␣ peptide (cyclin L1␣-specific antibody, amino acids 314 -369), or GST-cyclin L2␣ peptide (cyclin L2␣-specific antibody, amino acids 307-379).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were harvested 24 h after transfection for the enzymatic assays. ␤-Galactosidase and luciferase activities were measured using the Dual-Light Assay System (Applied Biosystems) (24). 3-9 transfected samples were measured in quadruplicate per data point.…”

Section: Methodsmentioning

confidence: 99%

“…RNPS1 is an SR protein that functions as a general activator of splicing, promotes alternative splicing in a substrate-specific manner, and is a component of the exon-exon junction complex. RNPS1 co-immunoprecipitates with CDK11 p110 , and both RNPS1 and CDK11 p110 are phosphorylated by CK2 (23,24). The general splicing factor 9G8, which also promotes the nucleocytoplasmic export of mRNA, co-immunoprecipitates with CDK11 p110 and is a CDK11 p110 substrate.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Characterization of Cyclin L1 and L2 Interactions with CDK11 and Splicing Factors

Loyer

Trembley

Grenet

et al. 2008

Journal of Biological Chemistry

Self Cite

122

137

View full text Add to dashboard Cite

Although it has been reported that cyclin L1␣ and L2␣ proteins interact with CDK11 p110 , the nature of the cyclin L transcripts, the formation of complexes between the five cyclin L and the three CDK11 protein isoforms, and the influence of these complexes on splicing have not been thoroughly investigated. Here we report that cyclin L1 and L2 genes generate 14 mRNA variants encoding six cyclin L proteins, one of which has not been described previously. Using cyclin L gene-specific antibodies, we demonstrate expression of multiple endogenous cyclin L proteins in human cell lines and mouse tissues. Moreover, we characterize interactions between CDK11 p110 , mitosis-specific CDK11 p58 , and apoptosis-specific CDK11 p46 with both cyclin L␣ and -␤ proteins and the co-elution of these proteins following size exclusion chromatography. We further establish that CDK11 p110 and associated cyclin L␣/␤ proteins localize to splicing factor compartments and nucleoplasm and interact with serine/arginine-rich proteins. Importantly, we also determine the effect of CDK11-cyclin L complexes on pre-mRNA splicing. Preincubation of nuclear extracts with purified cyclin L␣ and -␤ isoforms depletes the extract of in vitro splicing activity. Ectopic expression of cyclin L1␣, L1␤, L2␣, or L2␤ or active CDK11 p110 individually enhances intracellular intron splicing activity, whereas expression of CDK11 p58/p46 or kinase-dead CDK11 p110 represses splicing activity. Finally, we demonstrate that expression of cyclins L␣ and -␤ and CDK11 p110 strongly and differentially affects alternative splicing in vivo. Together, these data establish that CDK11 p110 interacts physically and functionally with cyclin L␣ and -␤ isoforms and SR proteins to regulate splicing.It has become apparent over the past decade that several cyclin-dependent kinases (CDKs) 4 and their cyclin regulatory partners participate in regulating mRNA production (1). Thus far, CDK7, CDK8, and CDK9 functions are ascribed to transcriptional initiation and elongation, and CDK12 (CrkRS) and CDK13 (CDC2L5) functions are related to pre-mRNA splicing (2-4). Interestingly, CDK11 p110 plays roles in both transcription and splicing, suggesting that this CDK may link the two processes (5, 6). In addition, the CDK11 p110 partner proteins cyclins L1 and L2 also influence splicing (7,8). Two distinct genes, Cdc2L1 and Cdc2L2 (acronym for Cell division control 2 Like), encode the human p110 and p58 PITSLRE protein kinases (9 -12). These kinases were renamed CDK11 p110 and CDK11 p58 when cyclins L1 and L2 were identified as regulatory subunits of CDK11 p110 (13). Expression of the CDK11 p110 isoforms is ubiquitous and constant throughout the cell cycle (11). In contrast, CDK11 p58 is expressed and functions specifically in G 2 /M via an internal ribosome entry site (IRES) located within the CDK11 p110 mRNA (14 -17). During apoptosis, a third isoform, CDK11 p46 , is generated by caspase-dependent cleavage of CDK11 p110 and CDK11 p58 , leaving the catalytic domain intact (18,19).A role for CDK11 p...

show abstract

Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases

et al. 2017

View full text Add to dashboard Cite

IMPORTANCE Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. OBJECTIVES To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. DESIGN, SETTING, AND PARTICIPANTS Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. MAIN OUTCOMES AND MEASURES The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. RESULTS Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. CONCLUSIONS AND RELEVANCE The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

show abstract

Activation of Pre-mRNA Splicing by Human RNPS1 Is Regulated by CK2 Phosphorylation

Cited by 50 publications

References 52 publications

Protein kinase CK2 interacts with the splicing factor hPrp3p

Protein kinase CK2 interacts with the splicing factor hPrp3p

Characterization of Cyclin L1 and L2 Interactions with CDK11 and Splicing Factors

Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases

Contact Info

Product

Resources

About