Disease relevance of SKY1

• SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line [1].
• In cross-resistance studies, we observed resistance of yeast sky1 Delta cells (i.e., cells from which the SKY1 gene had been disrupted) to cisplatin, carboplatin (but not oxaliplatin), doxorubicin and daunorubicin, and hypersensitivity to cadmium chloride and 5-fluorouracil [2].

High impact information on SKY1

• Here, we demonstrate a novel function of the single conserved SR protein kinase Sky1p in nuclear import in budding yeast [3].
• Strikingly, all RS domain-mediated interactions were abolished by SKY1 deletion and were rescuable by yeast or mammalian SR protein-specific kinases, indicating that phosphorylation has a far greater impact on RS domain interactions in vivo than in vitro [4].
• Using a transcriptional repression assay, we further showed that most LexA-SR fusion proteins depend on Sky1p to efficiently recognize the LexA binding site in a reporter, suggesting that molecular targeting of RS domain-containing proteins within the nucleus was also affected [4].
• The modeled complex combined with mutagenesis studies illustrate the molecular basis for substrate recognition by this kinase and suggest a mechanism by which SRPKs catalyze a sequential phosphorylation reaction of the consecutive RS dipeptide repeats characteristic of mammalian SRPK substrates [5].
• Because of the strict splice site consensus and near absence of alternative splicing in Saccharomyces cerevisiae, it had been thought that budding yeast would lack an SRPK and its substrates [6].

Biological context of SKY1

• Deletions of SKY1 or PTK2 in the Saccharomyces cerevisiae trk1Deltatrk2Delta mutant cells exert dual effect on ion homeostasis [7].
• These results suggest for the first time that 3' AG recognition may be subject to phosphorylation regulation by Sky1p during pre-mRNA splicing [8].
• In this study, using budding yeast Saccharomyces cerevisiae as a model organism to identify novel drug resistance genes, we found that disruption of the yeast gene SKY1 (serine/arginine-rich protein-specific kinase from budding yeast) by either transposon insertion or one-step gene replacement conferred cellular resistance to cisplatin [1].
• Inactivation of the Saccharomyces cerevisiae SKY1 gene induces a specific modification of the yeast anticancer drug sensitivity profile accompanied by a mutator phenotype [2].
• Sky1p and Ptk2p are protein kinases that regulate ion transport across the plasma membrane of Saccharomyces cerevisiae [7].

Anatomical context of SKY1

• Based on the modification of the anticancer drug sensitivity profile and our finding that sky1 Delta cells display a mutator phenotype, we propose that Sky1p might play a significant role in specific repair and/or tolerance pathways [2].

Associations of SKY1 with chemical compounds

• SKY1 disruption results in dramatically reduced uptake of spermine, spermidine, and putrescine [9].
• In conclusion, we identified NPR2 as a novel component involved in cell kill provoked by cisplatin and doxorubicin, and our data support the hypothesis that NPR2 and SKY1 may use mutual regulatory routes to mediate the cytotoxicity of these anticancer drugs [10].
• Therefore, we generated yeast npr2Delta sky1Delta double-knockout cells and performed clonogenic survival assays for cisplatin and doxorubicin, which revealed that NPR2 and SKY1 (SR-protein-specific kinase from budding yeast) are epistatic [10].
• We show here that deletion of SKY1 or PTK2 in trk1,2Delta cells increase spermine tolerance, implying Trk1,2p independent activity [7].
• Moreover, using sucrose density gradient analysis, we provide evidence that the import receptor Mtr10p, but not the SR protein kinase Sky1p, is involved in the timely regulated release of Npl3p from polysome-associated mRNAs [11].

Enzymatic interactions of SKY1

• Sky1p bound and phosphorylated Npl3 with a Km that was 2 orders of magnitude lower than a short peptide mimic representing the phosphorylation site and only proximal determinants [12].

Regulatory relationships of SKY1

• Phosphorylation by Sky1p promotes Npl3p shuttling and mRNA dissociation [13].

Other interactions of SKY1

• Two yeast kinases, SKY1 and PTK2, have been demonstrated to regulate polyamine tolerance [14].
• Mutation of the C-terminal RS to RA, or deletion of SKY1, results in the cytoplasmic accumulation of Npl3p [13].
• Nuclear import of Gbp2 is dependent on the receptor Mtr10 and the serine/arginine-specific protein kinase Sky1 [15].
• Cellular localization and phosphorylation of Hrb1p is independent of Sky1p [16].

Analytical, diagnostic and therapeutic context of SKY1

• Taking advantage of the single nonessential SR protein-specific kinase Sky1p in Saccharomyces cerevisiae, we investigated RS domain interactions in vivo using the two-hybrid assay [4].
• Nucleotide-induced conformational changes in the Saccharomyces cerevisiae SR protein kinase, Sky1p, revealed by X-ray crystallography [17].

References