Localization of Serine Kinases, SRPK1 (SFRSK1) and SRPK2 (SFRSK2), Specific for the SR Family of Splicing Factors in Mouse and Human Chromosomes

Wang, Huan You; Arden, Karen C.; Bermingham, John R.; Viars, Carrie S.; Lin, Wen; Boyer, Antonia; Fu, Xiang Dong

doi:10.1006/geno.1999.5770

Cited by 22 publications

(16 citation statements)

References 25 publications

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“…PF11_0156 clearly is an orthologue of human PRP4, a kinase that is associated with mRNA splicing and histone deacetylation and that is conserved in most eukaryotic genomes (including Schizosaccharomyces pombe , but not Saccharomyces cerevisiae ) [56,57]. Human SRPK1 phosphorylates the "Serine-Arginine-rich pre-mRNA splicing factors" called SR proteins, and homologues are conserved in all eukaryotic genomes [58,59]. Two P. falciparum kinases (PFC0105w and PFl4_0408) cluster with SPRK.…”

Section: Resultsmentioning

confidence: 99%

Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote

et al. 2004

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Background: Malaria, caused by the parasitic protist Plasmodium falciparum, represents a major public health problem in the developing world. The P. falciparum genome has been sequenced, which provides new opportunities for the identification of novel drug targets. Eukaryotic protein kinases (ePKs) form a large family of enzymes with crucial roles in most cellular processes; hence malarial ePKS represent potential drug targets. We report an exhaustive analysis of the P. falciparum genomic database (PlasmoDB) aimed at identifying and classifying all ePKs in this organism.

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Section: Resultsmentioning

confidence: 99%

Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote

et al. 2004

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“…Expression of SRPK1 transcripts in the intact pancreas has been described previously via Northern blot analysis (15,17), yet the precise cellular and subcellular localizations of the resultant protein within this organ remain unspecified. To resolve this issue, we have done immunohistochemistry on pancreatic tissue sections using a monoclonal antibody specific for SRPK1 (Fig.…”

Section: Srpk1 Expression In Normal and Neoplastic Pancreasmentioning

confidence: 99%

Targeting the RNA Splicing Machinery as a Novel Treatment Strategy for Pancreatic Carcinoma

et al. 2006

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Aberrant patterns of pre-mRNA splicing have been established for many human malignancies, yet the mechanisms responsible for these tumor-specific changes remain undefined and represent a promising area for therapeutic intervention. Using immunohistochemistry, we have localized the expression of a central splicing regulator, serine-arginine protein kinase 1 (SRPK1), to the ductular epithelial cells within human pancreas and have further shown its increased expression in tumors of the pancreas, breast, and colon. Small interfering RNA-mediated down-regulation of SRPK1 in pancreatic tumor cell lines resulted in a dose-dependent decrease in proliferative capacity and increase in apoptotic potential. Coordinately, the disruption of SRPK1 expression resulted in enhanced sensitivity of tumor cells to killing by gemcitabine and/or cisplatin. A dose-dependent reduction in the phosphorylation status of specific SR proteins was detected following the downregulation of SRPK1 and is likely responsible for the observed alterations in expression of proteins associated with apoptosis and multidrug resistance. These data support SRPK1 as a new, potential target for the treatment of pancreatic ductular cancer that at present remains largely unresponsive to conventional therapies. Furthermore, these results support the development of innovative therapies that target not only specific splice variants arising during tumorigenesis but also the splice regulatory machinery that itself may be abnormal in malignant cells.

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“…Serine-Arginine protein kinase 2 (SRPK2) belongs to a small protein kinase family that specifically phosphorylates serine residues of the serine-arginine (SR) rich motif on substrates (Wang et al, 1999; Wang et al, 1998). It is a cell cycle-regulated kinase that modulates the activity of the pre-mRNA alternative splicing machinery (Ngo et al, 2005; Zhong et al, 2009; Zhou et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

Wang

Liu

et al. 2017

Molecular Cell

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Summary Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and Tau, controlling the onset of pathogenesis of Alzheimer’s disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that Serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. Overexpression of phosphorylation mimetic (S226D) in young 3XTg mice strongly promoted APP and Tau fragmentation, and facilitated amyloid plaque deposits and neurofibrillary tangles (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreased APP and Tau proteolytic cleavage and attenuated AD pathologies and reversed cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis.

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Localization of Serine Kinases, SRPK1 (SFRSK1) and SRPK2 (SFRSK2), Specific for the SR Family of Splicing Factors in Mouse and Human Chromosomes

Cited by 22 publications

References 25 publications

Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote

Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote

Targeting the RNA Splicing Machinery as a Novel Treatment Strategy for Pancreatic Carcinoma

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer’s Disease

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