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First published online 13 April 2005
doi: 10.1242/dev.01825
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1 Department of Molecular and Cell Biology, Howard Hughes Medical Institute, 545
Life Sciences Addition, University of California at Berkeley, Berkeley, CA
94720-3200, USA
2 Department of Physiology and Biochemistry, Howard Hughes Medical Institute,
1550 4th Street, Room GD481, University of California, San Francisco, Box
0725, San Francisco, CA 94143-0725, USA
3 Fox Chase Cancer Center, Cellular and Developmental Biology Program, 333
Cottman Avenue, Philadelphia, PA 19111, USA
* Author for correspondence (e-mail: lai{at}fruitfly.org)
Accepted 3 March 2005
The receptor Notch and its ligands of the Delta/Serrate/LAG2 (DSL) family are the central components in the Notch pathway, a fundamental cell signaling system that regulates pattern formation during animal development. Delta is directly ubiquitinated by Drosophila and Xenopus Neuralized, and by zebrafish Mind bomb, two unrelated RING-type E3 ubiquitin ligases with common abilities to promote Delta endocytosis and signaling activity. Although orthologs of both Neuralized and Mind bomb are found in most metazoan organisms, their relative contributions to Notch signaling in any single organism have not yet been assessed. We show here that a Drosophila ortholog of Mind bomb (D-mib) is a positive component of Notch signaling that is required for multiple Neuralized-independent, Notch-dependent developmental processes. Furthermore, we show that D-mib associates physically and functionally with both Serrate and Delta. We find that D-mib uses its ubiquitin ligase activity to promote DSL ligand activity, an activity that is correlated with its ability to induce the endocytosis and degradation of both Delta and Serrate (see also Le Borgne et al., 2005). We further demonstrate that D-mib can functionally replace Neuralized in multiple cell fate decisions that absolutely require endogenous Neuralized, a testament to the highly similar activities of these two unrelated ubiquitin ligases in regulating Notch signaling. We conclude that ubiquitination of Delta and Serrate by Neuralized and D-mib is an obligate feature of DSL ligand activation throughout Drosophila development.
Key words: Mind bomb, Neuralized, Serrate, Delta, Notch signaling, Endocytosis
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