Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT.
Serine/arginine-rich (SR) proteins are important regulators of mRNA splicing. Several postsplicing activities have been described for a subset of shuttling SR proteins, including regulation of mRNA export and translation. Using the fibronectin gene to study the links between signal-transduction pathways and SR protein activity, we show that growth factors not only modify the alternative splicing pattern of the fibronectin gene but also alter translation of reporter messenger RNAs in an SR protein-dependent fashion, providing two coregulated levels of isoform-specific amplification. These effects are inhibited by specific small interfering RNAs against SR proteins and are mediated by the AKT kinase, which elicits opposite effects to those evoked by overexpressing SR protein kinases Clk and SRPK. These results show how SR protein activity is modified in response to extracellular stimulation, leading to a concerted regulation of splicing and translation.
Blaustein
Matías
M
Instituto de Fisiología, Biología Molecular y Neurociencias, Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Fisiología, Biología Molecular y Celular, Universidad de Buenos Aires, Ciudad Universitaria, Argentina.
Pelisch
Federico
F
Tanos
Tamara
T
Muñoz
Manuel J
MJ
Wengier
Diego
D
Quadrana
Leandro
L
Sanford
Jeremy R
JR
Muschietti
Jorge P
JP
Kornblihtt
Alberto R
AR
Cáceres
Javier F
JF
Coso
Omar A
OA
Srebrow
Anabella
A
D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D015398:Signal Transduction
D005353:Fibronectins; D006133:Growth Substances; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt