title: RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J.
abstract: The evolutionarily conserved Notch signal transduction pathway regulates fundamental cellular processes during embryonic development and in the adult. Ligand binding induces presenilin-dependent cleavage of the receptor and a subsequent nuclear translocation of the Notch intracellular domain (NICD). In the nucleus, NICD binds to the recombination signal sequence-binding protein J (RBP-J)/CBF-1 transcription factor to induce expression of Notch target genes. Here, we report the identification and functional characterization of RBP-J interacting and tubulin associated (RITA) (C12ORF52) as a novel RBP-J/CBF-1-interacting protein. RITA is a highly conserved 36 kDa protein that, most interestingly, binds to tubulin in the cytoplasm and shuttles rapidly between cytoplasm and nucleus. This shuttling RITA exports RBP-J/CBF-1 from the nucleus. Functionally, we show that RITA can reverse a Notch-induced loss of primary neurogenesis in Xenopus laevis. Furthermore, RITA is able to downregulate Notch-mediated transcription. Thus, we propose that RITA acts as a negative modulator of the Notch signalling pathway, controlling the level of nuclear RBP-J/CBF-1, where its amounts are limiting.
authors.affiliation: Institute of Biochemistry, Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Stephan Armin
authors.initials: SA
authors.lastname: Wacker
authors.forename: Cristobal
authors.initials: C
authors.lastname: Alvarado
authors.forename: Götz
authors.initials: G
authors.lastname: von Wichert
authors.forename: Uwe
authors.initials: U
authors.lastname: Knippschild
authors.forename: Jörg
authors.initials: J
authors.lastname: Wiedenmann
authors.forename: Karen
authors.initials: K
authors.lastname: Clauss
authors.forename: Gerd Ulrich
authors.initials: GU
authors.lastname: Nienhaus
authors.forename: Horst
authors.initials: H
authors.lastname: Hameister
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
authors.forename: Tilman
authors.initials: T
authors.lastname: Borggrefe
authors.forename: Walter
authors.initials: W
authors.lastname: Knöchel
authors.forename: Franz
authors.initials: F
authors.lastname: Oswald
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D018385:Centrosome / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis; D011485:Protein Binding; D021381:Protein Transport; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014404:Tubulin / Q000378:metabolism; D029867:Xenopus Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000235:genetics / Q000378:metabolism*
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008869:Microtubule-Associated Proteins; C555811:RITA1 protein, Xenopus; D051881:Receptor, Notch1; D051880:Receptors, Notch; D014404:Tubulin; D029867:Xenopus Proteins