Conserved proline-directed phosphorylation regulates SR protein conformation and splicing function

Keshwani, Malik M.; Aubol, Brandon E.; Fattet, Laurent; Ma, Chen‐Ting; Qiu, Jinsong; Jennings, Patricia A.; Fu, Xiang‐Dong; Adams, Joseph A.

doi:10.1042/bj20141373

Cited by 42 publications

(76 citation statements)

References 52 publications

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“…So the understanding of molecular mechanisms of ESCC can benefit patients very well. SRPK1, a highly conserved protein in eukaryotic organisms, is comprised of a PKC superfamily kinase domain and a spacer region that divides the kinase domain by half [6,7]. Some reports demonstrate the key role of SRPK1 in phosphorylation of specific amino acids of proteins rich in serinearginine repeats that is called as RS domain proteins [8].…”

Section: Introductionmentioning

confidence: 99%

The crucial role of SRPK1 in TGF-β-induced proliferation and apoptosis in the esophageal squamous cell carcinomas

Ren

Sheng

et al. 2015

Med Oncol

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In recent years, transforming growth factor-β (TGF-β) and the serine-arginine protein kinase 1 (SRPK1) have been recommended as a key signal mediator that is involved in oncogenesis. However, the mechanisms underlying TGF-β-SRPK1 pathway-mediated proliferation and apoptosis in the esophageal squamous cell carcinomas (ESCC) have not been well featured till now. We used immunohistochemistry, immunoblotting, and RT-PCR to assess the expression of SRPK1 in 120 cases of ESCC samples and cell lines. Subsequently, some in vitro assays were also applied where cells were administrated with TGF-β. We found that SRPK1 was highly expressed in ESCC tissues and acts as an independent prognostic factor for ESCC patients. In vitro studies indicated that overexpression of wild-type SRPK1 promoted ESCC cell proliferation, while overexpression of the kinase-dead mutant of SRPK1 or RNA interference against SRPK1 suppressed cell growth and enhanced apoptosis. The knockdown of SRPK1 also inhibited subcutaneous xenografts' growth of ESCC cells in nude mice. Furthermore, Western bolt analysis showed SRPK1 can activate Akt phosphorylation and inhibit JNK phosphorylation. In conclusion, SRPK1 mediates TGF-β-induced proliferation and apoptosis by regulating AKT and JNK in ESCC, which indicates TGF-β-SRPK1 pathway may be suggested as a useful target to affect the progression of ESCC.

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Section: Introductionmentioning

confidence: 99%

The crucial role of SRPK1 in TGF-β-induced proliferation and apoptosis in the esophageal squamous cell carcinomas

Ren

Sheng

et al. 2015

Med Oncol

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“…SR-25, as other SR proteins, is also rich in potential phosphorylation residues and motifs (29). Previous studies demonstrated that a specific conformation of the SR proteins is required for their protein-protein interactions or for their phosphorylation/dephosphorylation during the splicing cycle (32). However, the highly repetitive sequence composition and the presence of multiple proline residues in the SR domains of SR proteins indicate that they are rather unstructured (33).…”

Section: Sr-25 Is Upregulated By Cypa Overexpression In Vitromentioning

confidence: 89%

“…It can be speculated that the PPIase activity may be involved in the interaction between CypA and SR-25. SR proteins are phosphoproteins, and their phosphorylation status can affect their ability to interact with splicing complexes (21,32). SR-25, as other SR proteins, is also rich in potential phosphorylation residues and motifs (29).…”

Section: Sr-25 Is Upregulated By Cypa Overexpression In Vitromentioning

confidence: 99%

Interaction of cyclophilin A with a novel binding protein, SR-25, and characterization of their expression pattern in Chinese hepatocellular carcinoma patients

Chen

Lian

et al. 2016

Oncology Letters

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Abstract. Cyclophilin (Cyp) A has been reported to be overexpressed in the majority of cancer cells, including hepatocellular carcinoma (HCC). However, the biological functions of CypA in HCC are far from being understood. To determine the biological functions of CypA in HCC, the present study screened human fetal liver complementary DNA for proteins interacting with CypA using the yeast two-hybrid system. A nuclear protein, serine/arginine-rich (SR)-25, was isolated as a novel CypA-binding protein that is distinct from those previously described in the literature. Binding assays and co-immunoprecipitation confirmed the physical association between CypA and SR-25. The present study demonstrated that CypA may interact with SR-25 through its peptidyl-prolyl isomerase domain. In addition, CypA may induce the expression of SR-25 in Hep3B cells. The messenger RNA levels of CypA and SR-25 in HCC indicated that there was a significant correlation between the expression of CypA and the expression of SR-25 in HCC. It can be speculated that the interaction between CypA and SR-25 proteins may be involved in potential carcinogenic functions of CypA in HCC. Further studies will focus on elucidating in detail the molecular mechanisms of the interaction between CypA and SR-25.

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“…Although some splice events are known where one splicing factor is the dominant regulator, in many cases alternative splicing is determined by the sum of the activity of several splicing regulatory proteins (15,16). The activity of such proteins can be controlled by changes in expression or by posttranslational modifications that can control localization or RNA binding capability for example (17)(18)(19)(20)(21). Altered activity may then result in alternative splicing of several or many exons in a concerted manner, thus contributing to establish global splicing patterns, for example in a tissue-specific manner (9,(22)(23)(24)(25).…”

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confidence: 99%

Activation-Dependent TRAF3 Exon 8 Alternative Splicing Is Controlled by CELF2 and hnRNP C Binding to an Upstream Intronic Element

Schultz

Preußner

Bunse

et al. 2017

Molecular and Cellular Biology

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Cell-type-specific and inducible alternative splicing has a fundamental impact on regulating gene expression and cellular function in a variety of settings, including activation and differentiation. We have recently shown that activationinduced skipping of TRAF3 exon 8 activates noncanonical NF-B signaling upon T cell stimulation, but the regulatory basis for this splicing event remains unknown. Here we identify cis-and trans-regulatory elements rendering this splicing switch activation dependent and cell type specific. The cis-acting element is located 340 to 440 nucleotides upstream of the regulated exon and acts in a distance-dependent manner, since altering the location reduces its activity. A small interfering RNA screen, followed by cross-link immunoprecipitation and mutational analyses, identified CELF2 and hnRNP C as trans-acting factors that directly bind the regulatory sequence and together mediate increased exon skipping in activated T cells. CELF2 expression levels correlate with TRAF3 exon skipping in several model systems, suggesting that CELF2 is the decisive factor, with hnRNP C being necessary but not sufficient. These data suggest an interplay between CELF2 and hnRNP C as the mechanistic basis for activation-dependent alternative splicing of TRAF3 exon 8 and additional exons and uncover an intronic splicing silencer whose full activity depends on the precise location more than 300 nucleotides upstream of the regulated exon.KEYWORDS RNA binding proteins, RNA splicing S plicing-sensitive microarrays and transcriptome sequencing (RNA-Seq) technologies have led to the accumulation of enormous amounts of gene expression data from different cell types and tissues under various conditions. Such analyses have led to the conclusion that the majority of human genes are alternatively spliced and have shown strong differences in global splicing patterns under different conditions (1-3). Although these differences suggest a substantial contribution of alternative splicing to the regulation of gene expression, studies connecting alternative splicing and functionality are rare. Consequently, a functional impact of individual alternative splicing events on cellular functionality was demonstrated for only a few examples (4-7), and the function of most alternative splicing events remains unknown. However, a recent large-scale approach demonstrated that splice-isoforms of the same gene often have distinct protein-protein interaction profiles, further supporting the notion of distinct functionality (8).Another largely open question concerns splicing regulation: how are cell-typespecific splicing patterns established and maintained? Despite the identification of

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Conserved proline-directed phosphorylation regulates SR protein conformation and splicing function

Cited by 42 publications

References 52 publications

The crucial role of SRPK1 in TGF-β-induced proliferation and apoptosis in the esophageal squamous cell carcinomas

The crucial role of SRPK1 in TGF-β-induced proliferation and apoptosis in the esophageal squamous cell carcinomas

Interaction of cyclophilin A with a novel binding protein, SR-25, and characterization of their expression pattern in Chinese hepatocellular carcinoma patients

Activation-Dependent TRAF3 Exon 8 Alternative Splicing Is Controlled by CELF2 and hnRNP C Binding to an Upstream Intronic Element

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