The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration.
Alternative splicing of pre-messenger RNA (mRNA) is a critical stage of gene regulation in response to environmental stimuli. Here we show that DAZAP1, an RNA-binding protein involved in mammalian development and spermatogenesis, promotes inclusion of weak exons through specific recognition of diverse cis-elements. The carboxy-terminal proline-rich domain of DAZAP1 interacts with and neutralizes general splicing inhibitors, and is sufficient to activate splicing when recruited to pre-mRNA. This domain is phosphorylated by the MEK/Erk (extracellular signal-regulated protein kinase) pathway and this modification is essential for the splicing regulatory activity and the nuclear/cytoplasmic translocation of DAZAP1. Using mRNA-seq, we identify endogenous splicing events regulated by DAZAP1, many of which are involved in maintaining cell growth. Knockdown or over-expression of DAZAP1 causes a cell proliferation defect. Taken together, these studies reveal a molecular mechanism that integrates splicing control into MEK/Erk-regulated cell proliferation.
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Rajarshi
R
Choudhury
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Sreerupa Ghose
SG
Roy
1] Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA [2] Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Yihsuan S
YS
Tsai
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Ashutosh
A
Tripathy
1] Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Lee M
LM
Graves
1] Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Zefeng
Z
Wang
D017398:Alternative Splicing / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D005091:Exons / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D057809:HEK293 Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D016601:RNA-Binding Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
C412481:DAZAP1 protein, human; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D016601:RNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases