title: Fas-activated serine/threonine phosphoprotein (FAST) is a regulator of alternative splicing.
abstract: Fas-activated serine/threonine phosphoprotein (FAST) is a survival protein that is tethered to the outer mitochondrial membrane. In cells subjected to environmental stress, FAST moves to stress granules, where it interacts with TIA1 to modulate the process of stress-induced translational silencing. Both FAST and TIA1 are also found in the nucleus, where TIA1 promotes the inclusion of exons flanked by weak splice recognition sites such as exon IIIb of the fibroblast growth factor receptor 2 (FGFR2) mRNA. Two-hybrid interaction screens and biochemical analysis reveal that FAST binds to several alternative and constitutive splicing regulators, suggesting that FAST might participate in this process. The finding that FAST is concentrated at nuclear speckles also supports this contention. We show that FAST, like TIA1, promotes the inclusion of exon IIIb of the FGFR2 mRNA. Both FAST and TIA1 target a U-rich intronic sequence (IAS1) adjacent the 5' splice site of exon IIIb. However, unlike TIA1, FAST does not bind to the IAS1 sequence. Surprisingly, knockdown experiments reveal that FAST and TIA1 act independently of one another to promote the inclusion of exon IIIb. Mutational analysis reveals that FAST-mediated alternative splicing is separable from the survival effects of FAST. Our data reveal that nuclear FAST can regulate the splicing of FGFR2 transcripts.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Simarro
authors.forename: David
authors.initials: D
authors.lastname: Mauger
authors.forename: Kirsten
authors.initials: K
authors.lastname: Rhee
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pujana
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Kedersha
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cusick
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.forename: Mariano A
authors.initials: MA
authors.lastname: Garcia-Blanco
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis / Q000235:genetics; D015003:Yeasts; D019014:fas Receptor / Q000502:physiology*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor; C095367:FASTK protein, human; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017346:Protein Serine-Threonine Kinases