RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J.

Institute of Biochemistry, Department of Internal Medicine I, University of Ulm, Ulm, Germany.

The EMBO journal 2011 Jan 5

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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.

Citation

Stephan Armin Wacker, Cristobal Alvarado, Götz von Wichert, Uwe Knippschild, Jörg Wiedenmann, Karen Clauss, Gerd Ulrich Nienhaus, Horst Hameister, Bernd Baumann, Tilman Borggrefe, Walter Knöchel, Franz Oswald. RITA, a novel modulator of Notch signalling, acts via nuclear export of RBP-J. The EMBO journal. 2011 Jan 5;30(1):43-56