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Regulation of Notch signalling by non-visual β-arrestin

Nature Cell Biology volume 7, pages 1191–1201 (2005)Cite this article

An Erratum to this article was published on 02 December 2005

Abstract

Signalling activity of the Notch receptor, which plays a fundamental role in metazoan cell fate determination, is controlled at multiple levels. We uncovered a Notch signal-controlling mechanism that depends on the ability of the non-visual β-arrestin, Kurtz (Krz), to influence the degradation and, consequently, the function of the Notch receptor. We identified Krz as a binding partner of a known Notch-pathway modulator, Deltex (Dx), and demonstrated the existence of a trimeric Notch–Dx–Krz protein complex. This complex mediates the degradation of the Notch receptor through a ubiquitination-dependent pathway. Our results establish a novel mode of regulation of Notch signalling and define a new function for non-visual β-arrestins.

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Figure 1: The Krz and Dx proteins interact.
Figure 2: Genetic interactions between dx and krz mutations.
Figure 3: Krz, Dx and Notch colocalize and form a trimeric complex.
Figure 4: Loss of krz upregulates Notch protein levels.
Figure 5: Upregulation of markers of Notch activity in krz mutant clones.
Figure 6: Coexpression of Krz and Dx results in the reduction of Notch protein levels in vivo.
Figure 7: Krz and Dx synergistically affect the stability of Notch.
Figure 8: Krz and Dx downregulate Notch activity and enhance Notch ubiquitination.

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Acknowledgements

The authors wish to thank their colleagues D. Finley, M. Baron, R. Lake, M. Kankel and L. Grimm for helpful discussions about the manuscript. We are also grateful to M. Gonzalez-Gaitan and H. Chang for their comments and reagents. krz alleles were kindly provided by R. Davis and the dx152 allele was a gift from K. Matsuno. The anti-EGFR antibody was a gift from P. Rorth. R. Fehon provided a ubiquitination assay protocol and an HS–HA–Ub construct. pMT–Flag–UbWT and pMT–Flag–UbMONO were a gift from S. Bray. The GFP–Sec61 construct was a gift from G. Voeltz. Several fly lines were provided by the Bloomington Drosophila Stock Center, and some of the antibodies used in this work were obtained from the Developmental Studies Hybridoma Bank, Iowa. This work was supported by grants NS26084, GM62931 and CA098402 to S.A.-T. A.V. was supported by a postdoctoral fellowship from the Massachusetts General Hospital Fund for Medical Discovery.

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Author notes

  1. Alexey Veraksa

    Present address: Biology Department, University of Massachusetts Boston, Boston, MA, 02125, USA

  2. Ashim Mukherjee and Alexey Veraksa: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Massachusetts General Hospital Cancer Center, Charlestown, 02129, MA, USA

    Ashim Mukherjee, Alexey Veraksa & Spyros Artavanis-Tsakonas

  2. Cellzome AG, Heidelberg, 69117, Germany

    Andreas Bauer

  3. Institut Curie, Inserm U-528, Paris, 75248, Cedex, 05, France

    Carine Rosse & Jacques Camonis

  4. Collège de France, 11 place Marcelin Berthelot, Paris, 75231, Cedex, 05, France

    Spyros Artavanis-Tsakonas

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Correspondence to Spyros Artavanis-Tsakonas.

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Mukherjee, A., Veraksa, A., Bauer, A. et al. Regulation of Notch signalling by non-visual β-arrestin. Nat Cell Biol 7, 1191–1201 (2005). https://doi.org/10.1038/ncb1327

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