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Lai EC , Roegiers F , Qin X , Jan YN , Rubin GM
The ubiquitin ligase Drosophila mind bomb promotes notch signaling by regulating the localization and activity of Serrate and Delta
Development. 2005 ;132(10) :2319-2332
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Abstract
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.
Notes
09501991 (ISSN) Cited By: 13; Export Date: 25 May 2006; Source: Scopus CODEN: DEVPE; DOI: 10.1242/dev.01825 Language of Original Document: English Correspondence Address: Lai, E.C.; Department of Molecular and Cell Biology; Howard Hughes Medical Institute; University of California at Berkeley; 545 Life Sciences Addition Berkeley, CA 94720-3200, United States; email: lai@fruitfly.org Chemicals/CAS: ubiquitin protein ligase, 134549-57-8, delta protein; DNA Primers; Drosophila Proteins; Membrane Proteins; Mind bomb protein, Drosophila, EC 6.3.2.19; neur protein, Drosophila, EC 6.3.2.19; notch receptors; Serrate protein, 134324-36-0; Ubiquitin-Protein Ligases, EC 6.3.2.19 References: Abdelilah-Seyfried, S., Chan, Y.M., Zeng, C., Justice, N.J., Younger-Shepherd, S., Sharp, L.E., Barbel, S., (...), Jan, Y.N., A gain-of-function screen for genes that affect the development of the Drosophila adult external sensory organ (2000) Genetics, 155, pp. 733-752; Bellen, H.J., Levis, R.W., Liao, G., He, Y., Carlson, J.W., Tsang, G., Evans-Holm, M., (...), Rubin, G.M., The BDGP gene disruption project: Single transposon insertions associated with 40% of Drosophila genes (2004) Genetics, 167, pp. 761-781; Bishop, S.A., Klein, T., Arias, A.M., Couso, J.P., Composite signalling from Serrate and Delta establishes leg segments in Drosophila through Notch (1999) Development, 126, pp. 2993-3003; Boulianne, G.L., de la Concha, A., Campos-Ortega, J.A., Jan, L.Y., Jan, Y.N., The Drosophila neurogenic gene neuralized encodes a novel protein and is expressed in precursors of larval and adult neurons (1991) EMBO J., 10, pp. 2975-2983; Chen, N., Greenwald, I., The Lateral Signal for LIN-12/Notch in C. elegans Vulval Development Comprises Redundant Secreted and Transmembrane DSL Proteins (2004) Dev. 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