Alternative splicing regulation by interaction of phosphatase PP2Cgamma with nucleic acid-binding protein YB-1.
Kinases and phosphatases participate in precursor messenger RNA (pre-mRNA) splicing regulation, but their precise roles and the identities of their cofactors and substrates remain poorly understood. The human Ser/Thr phosphatase PP2Cgamma promotes spliceosome assembly. We show that PP2Cgamma's distinctive acidic domain is essential for its activity in splicing and interacts with YB-1, a spliceosome-associated factor. Moreover, PP2Cgamma is a phosphoprotein in vivo, and its acidic domain is phosphorylated under splicing conditions in vitro. PP2Cgamma phosphorylation enhances its interaction with YB-1 and is reversed by the phosphatase in cis. PP2Cgamma knockdown leaves constitutive splicing unaffected but inhibits cell proliferation and affects alternative splicing of CD44, a YB-1 target. This effect on splicing regulation is mediated by PP2Cgamma's acidic domain, which is essential to promote inclusion of CD44 exons v4 and v5 in vivo. We propose that PP2Cgamma modulates alternative splicing of specific pre-mRNAs coregulated by YB-1.
Allemand
Eric
E
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
Hastings
Michelle L
ML
Murray
Michael V
MV
Myers
Michael P
MP
Krainer
Adrian R
AR
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D017434:Protein Structure, Tertiary / Q000235:genetics; D012322:RNA Precursors / Q000378:metabolism; D051840:Y-Box-Binding Protein 1
D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D009687:Nuclear Proteins; D012322:RNA Precursors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C