Serine-arginine protein kinases: a small protein kinase family with a large cellular presence

Abstract

History of the discovery of the serine-arginine protein kinase (SPRK) familyThe first serine-arginine (SR) protein kinase to be purified and characterized was named SRPK1, for SR-protein-specific kinase 1 [1,2]. It was isolated during a search for the activity that phosphorylates SR splicing factors (also named SR proteins) during mitosis. SRPK1 was shown to phosphorylate SR proteins in a cell-cycle regulated manner, to affect SR protein localization and to inhibit splicing when added in large quantities to a cell-free splicing assay [1,2]. The SRPK1 cDNA was cloned, revealing that the Schizosaccharomyces pombe SRPK1 orthologue, Dsk1, had already been cloned and partially characterized as a kinase with cell cycle-dependent phosphorylation and subcellular localization [3]. The SRPK1 and Dsk1 nucleotide sequencing identified a domain interrupting the kinase catalytic site into two structural entities, Serine-arginine protein kinases (SPRKs) constitute a relatively novel subfamily of serine-threonine kinases that specifically phosphorylate serine residues residing in serine-arginine ⁄ arginine-serine dipeptide motifs. Fifteen years of research subsequent to the purification and cloning of human SRPK1 as a SR splicing factor-phosphorylating protein have lead to the accumulation of information on the function and regulation of the different members of this family, as well as on the genomic organization of SRPK genes in several organisms. Originally considered to be devoted to constitutive and alternative mRNA splicing, SRPKs are now known to expand their influence to additional steps of mRNA maturation, as well as to other cellular activities, such as chromatin reorganization in somatic and sperm cells, cell cycle and p53 regulation, and metabolic signalling. Similarly, SRPKs were considered to be constitutively active kinases, although several modes of regulation of their function have been demonstrated, implying an elaborate cellular control of their activity. Finally, SRPK gene sequence information from bioinformatics data reveals that SRPK gene homologs exist either in single or multiple copies in every single eukaryotic organism tested, emphasizing the importance of SRPK protein function for cellular life.Abbreviations CDK, cyclin dependent kinase; Clk, CDK-like kinase; CK2, casein kinase 2; FOXO1, forkhead box protein O1; HBV, hepatitis B virus; HP1, heterochromatin protein 1; Hsp, heat shock protein; LBR, lamin B receptor; NRF-1, nuclear respiratory factor-1; PGC-1, peroxisome proliferator activated receptor c coactivator-1; RS, arginine-serine; SAFB, scaffold attachment factor B; SR, serine-arginine; SRPK, serine-arginine protein kinase.

Distribution of SRPK1 in human brain

“…SRPKs (serine/arginine protein kinases), that specifically phosphorylate serine residues residing in SR/RS dipeptide motifs, constitute a conserved family of serine/threonine kinases, comprising more than 50 members that have been identified in the genomes of mammals, fungi, insects, nematode, and plants (Giannakouros et al, 2011). The vast majority of the functional studies concerning mammalian SRPKs were based on SRPK1.…”

Human Papillomavirus Type 1 E1^E4 Protein Is a Potent Inhibitor of the Serine-Arginine (SR) Protein Kinase SRPK1 and Inhibits Phosphorylation of Host SR Proteins and of the Viral Transcription and Replication Regulator E2

“…They have also been shown to associate with small nuclear ribonucleoproteins involved in spliceosome assembly (30). Furthermore, SRPKs have also been shown to phosphorylate the RS domains present in proteins that are not directly linked to pre-mRNA metabolism, suggesting that the kinases have diverse functions in the cell (25).…”

“…SRPK1 is one of a family of serine-threonine kinases (SRPK1a, SRPK1 to -3), which specifically phosphorylate serine residues in serine-arginine/arginine-serine (SR/RS) dipeptide motifs (24,25). The most studied substrates of these kinases have been the RNA-binding SR-rich proteins involved in multiple stages of mRNA maturation, including constitutive and alternative splicing, mRNA transport from the nucleus, and mRNA translation.…”

“…SRPKs have a predominantly cytoplasmic localization, where they phosphorylate SR proteins and facilitate their nuclear import (26). The kinases can translocate into the nucleus following stress, or other signals, and during the cell cycle (25,27,28). Here they are known to target substrates found in nuclear speckles causing their release and redistribution to the cytoplasm (29).…”

Role of RRV ORF52 in Virion Maturation

“…An additional study, using a yeast-two hybrid approach, identified several cellular proteins that interacted with BLRF2 including Serine/Arginine-rich protein kinase 2 (SRPK2) (268). SRPK2 is part of a larger family of serine/arginine kinases that phosphorylate serine residues in arginine-serine (RS) motifs and play critical roles in pre-mRNA splicing, acting as non-small nuclear ribonuclearprotein (snRNP) factors ( (329) and reviewed in (98,109)). Additionally, SRPK2 induces cell cycle progression by increasing cyclin A1 expression in hematopoietic cells (139) and apoptosis in neurons by increasing cyclin D1 (138).…”