title: Release of SR Proteins from CLK1 by SRPK1: A Symbiotic Kinase System for Phosphorylation Control of Pre-mRNA Splicing.
abstract: Phosphorylation has been generally thought to activate the SR family of splicing factors for efficient splice-site recognition, but this idea is incompatible with an early observation that overexpression of an SR protein kinase, such as the CDC2-like kinase 1 (CLK1), weakens splice-site selection. Here, we report that CLK1 binds SR proteins but lacks the mechanism to release phosphorylated SR proteins, thus functionally inactivating the splicing factors. Interestingly, CLK1 overcomes this dilemma through a symbiotic relationship with the serine-arginine protein kinase 1 (SRPK1). We show that SRPK1 interacts with an RS-like domain in the N terminus of CLK1 to facilitate the release of phosphorylated SR proteins, which then promotes efficient splice-site recognition and subsequent spliceosome assembly. These findings reveal an unprecedented signaling mechanism by which two protein kinases fulfill separate catalytic features that are normally encoded in single kinases to institute phosphorylation control of pre-mRNA splicing in the nucleus.
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Brandon E
authors.initials: BE
authors.lastname: Aubol
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Guowei
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Malik M
authors.initials: MM
authors.lastname: Keshwani
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Maliheh
authors.initials: M
authors.lastname: Movassat
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Fattet
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Klemens J
authors.initials: KJ
authors.lastname: Hertel
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: j2adams@ucsd.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Adams
mesh_terms: D002384:Catalysis; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000378:metabolism; D017381:Spliceosomes / Q000201:enzymology* / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D012322:RNA Precursors; D012333:RNA, Messenger; D017412:Ribonucleoprotein, U1 Small Nuclear; D055544:beta-Globins; C066780:Clk dual-specificity kinases; C087728:SRPK1 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases