UHMK1 is a splicing regulatory kinase
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA821472 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18539052_1.fastq.gz | Fastqsanger.gz | |||
| SRR18539052_2.fastq.gz | Fastqsanger.gz | |||
| SRR18539053_1.fastq.gz | Fastqsanger.gz | |||
| SRR18539053_2.fastq.gz | Fastqsanger.gz | |||
| SRR18539054_1.fastq.gz | Fastqsanger.gz |
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Project description:The U2AF Homology Motif Kinase 1 (UHMK1) is the only kinase that contains the U2AF homology motif (UHM), a common protein interaction domain among splicing factors. Through this motif, UHMK1 interacts with the splicing factors SF1 and SF3B1, known to participate in early steps of spliceosome assembly and 3’ splice site recognition. Also, UHMK1 phosphorylates these splicing factors in vitro. Despite that, the involvement of UHMK1 in RNA processing has never been demonstrated. Here, we submitted UHMK1-overexpressing or -depleted NIH3T3 cells RNAseq analysis to evaluate UHMK1 contribution to gene expression and splicing.
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Project description:The U2AF Homology Motif Kinase 1 (UHMK1) is the only kinase that contains the U2AF homology motif (UHM), a common protein interaction domain among splicing factors. Through this motif, UHMK1 interacts with the splicing factors SF1 and SF3B1, known to participate in the 3’ splice site recognition and early steps of spliceosome assembly. Also, UHMK1 phosphorylates these splicing factors in vitro. However, the involvement of UHMK1 in RNA processing has not previously been demonstrated. Here, we used global phosphoproteomics to identify novel putative substrates in UHMK1-overexpressing or -depleted (knockdown) NIH3T3 cells and better characterize the function of this kinase in splicing and other biological processes.
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Project description:The protein kinase KIS (product of the gene UHMK1) is expressed during mouse brain development and is proposed to control gene expression through the phosphorylation of splicing factor SF1. We compared the expression of transcripts in wild type and KIS-ko newborn mouse brain (females) using affymetrix exon 1st arrays.
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Project description:The protein kinase KIS (product of the gene UHMK1) is expressed during mouse brain development and is proposed to control gene expression through the phosphorylation of splicing factor SF1. We compared the expression of transcripts in wild type and KIS-ko newborn mouse brain (females) using affymetrix exon 1st arrays. Six pairs of wildtype and KIS-ko brains from littermate female newborn mice were processed for Affymetrix exon 1st array hybridization. Analysis was performed at the exon level using PLIER normalisation and the Affymetrix Expression Console.
2012-09-05 | E-GEOD-38097 | biostudies-arrayexpress
Project description:Functional characterization of splicing regulatory elements
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Project description:The impact of the kinase UHMK1 on liver cancer cells is unknown. In order to identify UHMK1-dependent genes, UHMK1 was inhibited by siRNA in comparison to nonsense-siRNA-transfected cells.
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Project description:Acute Myeloid Leukemia (AML) is a blood cancer complicated by acquired drug resistance, disease relapse, and low overall survival rates. Combination therapies using multiple targeted inhibitors can effectively treat AML patients. However, combination treatments are limited by the number of useable targets and our ability to create rational pairings using complimentary molecular mechanisms. Here, we used a human kinase domain-targeted CRISPR screen to identify histone H3 associated protein kinase (HASPIN) as a significant, understudied dependency in AML. HASPIN depletion significantly reduced growth rate, induced a cell cycle arrest, and dysregulated transcription in AML. A proteomics datamining study characterized splicing factors as major HASPIN kinase substrates and highlighted HASPIN’s role as a splicing regulatory kinase. Accordingly, HASPIN depletion strongly dysregulated splicing and inversed aberrant, pro-leukemic splicing programs in AML patients. HASPIN inhibitor CHR-6494 effectively reduced cell viability across AML subtypes while sparing healthy cells. Furthermore, a novel combination therapy consisting of CHR-6494 and BCL-2 inhibitor Venetoclax synergistically reduced AML cell viability and resensitized Venetoclax-resistant AMLs to treatment. Our study presents HASPIN kinase as a novel, therapeutic target for AML, underscores an underappreciated role in splicing regulation, and proposes a viable combination treatment for clinical use.
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Project description:Glycogen Synthase Kinase-3 (GSK-3) is a constitutively active, ubiquitously expressed protein kinase that regulates multiple signaling pathways. Over 100 putative GSK-3 substrates have been reported in diverse cell types based on in vitro kinase assays or genetic and pharmacological manipulation of GSK-3. Many more have been predicted based on a recurrent GSK-3 consensus motif, but this prediction has not been tested by analyzing the GSK-3 phosphoproteome. We used stable isotope labeling of amino acids in culture (SILAC) and mass spectrometry to analyze the repertoire of GSK-3 dependent substrates in mouse embryonic stem cells (ESCs). A comparison of wild-type and Gsk3a;Gsk3b knockout (DKO) ESCs revealed prominent GSK-3-dependent phosphorylation of multiple splicing factors and regulators of RNA biosynthesis, as well as proteins that regulate transcription, translation, and cell division. We demonstrate direct, GSK-3-dependent phosphorylation of the splicing factors RBM8A and PSF as well as the nucleolar protein NPM1. RNA sequencing to compare the transcriptomes of wild-type and Gsk3 DKO ESCs identified more than 210 genes that are alternatively spliced in a GSK-3-dependent manner, supporting a broad role for GSK-3 in regulating alternative splicing. Overall, this study provides the first unbiased analysis of the GSK-3 phosphoproteome and strong evidence for GSK-3 as a regulator of alternative splicing.
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Project description:RNA binding protein-RNA interactions mediate a variety of processes including pre-mRNA splicing, translation, decay, polyadenylation and many others. Previous high -throughput studies have characterized general sequence features associated with increased and decreased splicing of certain exons, but these studies are limited by not knowing the mechanisms underlying these associations. Here we utilize ENCODE data from diverse data modalities to identify functional splicing regulatory elements and their associated RNA binding proteins (RBPs). We identify features which make splicing events more sensitive to depletion of RBPs, as well as which RBPs act as splicing regulators sensitive tupon RBP depletion. To analyze the sequence determinants underlying RBP-RNA interactions impacting splicing, we assay tens of thousands of sequence variants in a high-throughput splicing reporter called Vex-seq and confirm a small subset in their endogenous loci using CRISPR base editors. Finally, we leverage other large transcriptomic datasets to confirm the importance of RBPs which we designed experiments around and identify additional RBPs which may act as additional splicing regulators of the exons studied.
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Project description:Pre-mRNA splicing relies on the still poorly understood dynamic interplay between more than 150 protein components of the Spliceosome, and the steps at which splicing can be regulated remain largely unknown. Here we systematically analyze the effect of knocking down the components of the splicing machinery on alternative splicing events relevant for cell proliferation and apoptosis and use this information to reconstruct a network of functional interactions. The network accurately captures well-established physical and functional associations and identifies new, revealing remarkable regulatory potential of core spliceosomal components, related to the order and duration of their recruitment during Spliceosome assembly. In contrast with standard models of regulation at early events of splice site recognition, factors involved in catalytic activation of the Spliceosome display regulatory properties. The network also sheds light on the antagonism between hnRNP C and U2AF and on targets of anti-tumor drugs, and can be widely used to identify mechanisms of splicing regulation. RNA from 3 biological replicates of 72 hours knockdowns of human IK or SMU1 and a control set were used. Changes between the control and knockdowns were measured based on using a splice-junction array (Affymetrix HJAY).
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