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

doi:10.1006/geno.1999.5770

Genomics

Volume 57, Issue 2, 15 April 1999, Pages 310-315

https://doi.org/10.1006/geno.1999.5770 Get rights and content

Abstract

The serine- and arginine-rich (SR) splicing factors play an important role in both constitutive and alternative pre-mRNA splicing, and the functions of these splicing factors are regulated by phosphorylation. We have previously characterized SRPK1 (SFRSK1) and SRPK2 (SFRSK2), which are highly specific protein kinases for the SR family of splicing factors. Here we report the chromosomal localization of the mouse and human genes for both kinases. SRPK1 probes detected two loci that were mapped to mouse Chromosomes 17 and X using The Jackson Laboratory interspecific backcross DNA panel, and SRPK2 probes identified a single locus on mouse Chromosome 5. Using a somatic cell hybrid mapping panel and by fluorescencein situhybridization, SRPK1 and SRPK2 were respectively mapped to human chromosomes 6p21.2–p21.3 (a region of conserved synteny to mouse Chromosome 17) and 7q22–q31.1 (a region of conserved synteny to mouse Chromosome 5). In addition, we also found multiple SRPK-related sequences on other human chromosomes, one of which appears to correspond to a SRPK2 pseudogene on human chromosome 8.

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Cited by (16)

Delta-Secretase Phosphorylation by SRPK2 Enhances Its Enzymatic Activity, Provoking Pathogenesis in Alzheimer's Disease
2017, Molecular Cell
Citation Excerpt :
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., 1998, 1999).
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 a phosphorylation mimetic (S226D) in young 3xTg mice strongly promotes APP and tau fragmentation and facilitates amyloid plaque deposits and neurofibrillary tangle (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreases APP and tau proteolytic cleavage, attenuates AD pathologies, and reverses cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis.
The N-terminal fragment from caspase-cleaved serine/arginine protein-specific kinase2 (SRPK2) translocates into the nucleus and promotes apoptosis
2011, Journal of Biological Chemistry
Citation Excerpt :
SRPK1 and SRPK2 are highly specific kinases for the SR family of splicing factors. SRPK1 is predominantly expressed in pancreas, whereas SRPK2 is highly expressed in brain, although both are coexpressed in other human tissues and in many experimental cell lines (3). The SRPK family of kinases, containing bipartite kinase domains separated by a unique spacer, is mainly localized in the cytoplasm, which is critical for nuclear import of SR proteins in a phosphorylation-dependent manner.
SRPK2 belongs to a family of serine/arginine (SR) protein-specific kinases (SRPKs), which phosphorylate SR domain-containing proteins in the nuclear speckles and mediate the pre-mRNA splicing. Previous studies have shown that SRPK2 plays a pivotal role in cell proliferation and apoptosis. However, how SRPK2 is regulated during the apoptosis is unclear. Here, we show that SRPK2 is cleaved by caspases at Asp-139 and -403 residues. Its N terminus cleaved product translocates into the nucleus and promotes VP16-induced apoptosis. Akt phosphorylation of SRPK2 prevents its apoptotic cleavage by caspases. 14-3-3β, the binding partner of Akt-phosphorylated SRPK2, further protects it from degradation. Hence, our results suggest that the N-terminal domain of SRPK2 cleaved by caspases translocates into the nucleus, where it promotes chromatin condensation and apoptotic cell death.
The ratio of SRPK1/SRPK1a regulates erythroid differentiation in K562 leukaemic cells
2010, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
The SRPK family is represented by four members in humans: SRPK1 (named also SRPK1 isoform 2 according to UniProtKB/Swiss-Prot Q96SB4), SRPK1a (named also SRPK1 isoform 1 according to UniProtKB/Swiss-Prot Q96SB4), SRPK2 and SRPK3. SRPK1 was mapped to chromosome 6p21.2–p21.3 [3]. Splicing out of a 513-bp segment, which is located between the first two exons of the SRPK1 locus, results in the production of SRPK1, whereas splicing in of the 513-bp segment yields its isoform SRPK1a [2].
SRPK1, the prototype of the serine/arginine family of kinases, has been implicated in the regulation of multiple cellular processes such as pre-mRNA splicing, chromatin structure, nuclear import and germ cell development. SRPK1a is a much less studied isoform of SRPK1 that contains an extended N-terminal domain and so far has only been detected in human testis. In the present study we show that SRPK1 is the predominant isoform in K562 cells, with the ratio of the two isoforms being critical in determining cell fate. Stable overexpression of SRPK1a induces erythroid differentiation of K562 cells. The induction of globin synthesis was accompanied by a marked decrease in proliferation and a significantly reduced clonogenic potential. Small interfering RNA-mediated down-regulation of SRPK1 in K562 cells results similarly in a decrease in proliferative capacity and induction of globin synthesis. A decreased SRPK1/SRPK1a ratio is also observed upon hemin/DMSO-induced differentiation of K562 cells as well as in normal human erythroid progenitor cells. Mass spectrometric analysis of SRPK1a-associated proteins identified multiple classes of RNA-binding proteins including RNA helicases, heterogeneous nuclear ribonucleoproteins, ribosomal proteins, and mRNA-associated proteins. Several of the SRPK1a-copurifying proteins have been previously identified in ribosomal and pre-ribosomal complexes, thereby suggesting that SRPK1a may play an important role in linking ribosomal assembly and/or function to erythroid differentiation in human leukaemic cells.
Cloning and Characterization of an Alternatively Spliced Form of SR Protein Kinase 1 that Interacts Specifically with Scaffold Attachment Factor-B
2001, Journal of Biological Chemistry
Citation Excerpt :
However, one of the clones contained an insertion of 513 bp between AAA (encoding lysine, the fourth amino acid of SRPK1) and GTG (encoding valine, the fifth amino acid of SRPK1), which is absent from the known sequence of SRPK1 (see Figs.1and 2). Because it is well documented that human SRPK1 is mapped to chromosome 6p21.2-p21.3 (41) and the genomic sequence is available (EMBL data bank, locus HS422H11, accession number Z99128) we compared the sequence of the isolated clone with the genomic sequence. The sequence alignment revealed that the SRPK1 gene comprises 16 exons (Fig. 2 A, see also EMBL data bank, locus HS422H11, accession number Z99128, gene = dJ422H11.1).
Serine/arginine protein kinases have been conserved throughout evolution and are thought to play important roles in the regulation of mRNA processing, nuclear import, germline development, polyamine transport, and ion homeostasis. Human SRPK1, which was first identified as a kinase specific for the SR family of splicing factors, is located on chromosome 6p21.2-p21.3. We report here the cloning and characterization of SRPK1a, which is encoded by an alternatively processed transcript derived from the SRPK1gene. SRPK1a contains an insertion of 171 amino acids at its NH₂-terminal domain and is similar to SRPK1 in substrate specificity and subcellular localization. Moreover, both isoforms can induce alternative splicing of human tau exon 10 in transfected cells. Using the yeast two-hybrid assay, we found that the extended NH₂-terminal domain of SRPK1a interacts with Scaffold Attachment Factor-B, a nuclear scaffold-associated protein. Confirmation of this interaction was provided by in vitrobinding assays, as well as by co-immunoprecipitation from 293T cells doubly transfected with SRPK1a and SAF-B. Our studies suggest that different SRPK family members are uniquely regulated and targeted and thus the multiple SRPK kinases present in higher eukaryotes may perform specialized and differentiable functions.
The BRD4-SRPK2-SRSF2 signal modulates the splicing efficiency of ACSL3 pre-mRNA and influences erastin-induced ferroptosis in osteosarcoma cells
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^☆: M. J. Barch

¹: To whom correspondence should be addressed. Telephone: (619) 534-4937. Fax: (619) 534-8549. E-mail:[email protected].

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

Abstract

Genomics

Genomics

J. Biol. Chem.

Biochem. Biophy. Res. Commun.

Genomics

Genomics

The receptors for prolactin and growth hormone are localized in the same region of human chromosome 5

Cytogenet. Cell Genet.

FBP WW domains and the ABL SH3 domains bind to a specific class of proline-rich ligands

EMBO J.

Both phosphorylation and dephosphorylation of ASF/SF2 are required for pre-mRNA splicing in vitro

RNA

The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution

EMBO J.

Specific commitment of different pre-mRNAs to splicing by single SR proteins

Nature

The superfamily of arginine/serine-rich splicing factors

RNA

A serine kinase regulates intracellular localization of splicing factors in the cell cycle

Nature

Purification and characterization of a kinase specific for the serine- and arginine-rich pre-mRNA splicing factors

Proc. Natl. Acad. Sci. USA

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