A complex signaling pathway regulates SRp38 phosphorylation and pre-mRNA splicing in response to heat shock.
Although pre-mRNA splicing is known to be regulated by cell signaling, the underlying mechanisms are poorly understood. SRp38 is a member of the SR protein family and, when dephosphorylated, functions as a general and potent splicing repressor in response to heat shock. Here we show that SRp38 is dephosphorylated by the phosphatase PP1, which is activated by dissociation of its inhibitors, including NIPP1. PP1 is targeted to SRp38 through direct interaction via its arginine/serine-rich (RS) domain. The specific dephosphorylation of SRp38 and not other SR proteins is determined largely by the low activities of SR protein kinases for it compared to other SR proteins. Finally, we show that 14-3-3 proteins associate with SRp38 and protect it from dephosphorylation under nonstress conditions, but dissociate upon heat shock. Together, our study delineates a complex mechanism involving multiple factors by which a stress signaling pathway regulates protein phosphorylation and, in turn, pre-mRNA splicing.
Shi
Yongsheng
Y
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Manley
James L
JL
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004722:Endoribonucleases / Q000378:metabolism; D018869:Heat-Shock Response / Q000502:physiology*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction / Q000502:physiology*
D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C115188:SRSF10 protein, human; D000068103:Serine-Arginine Splicing Factors; D004722:Endoribonucleases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C097081:PPP1R8 protein, human