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Molecular and Cellular Biology, April 2005, p. 2899-2909, Vol. 25, No. 8
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.8.2899-2909.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Numb Proteins Specify Asymmetric Cell Fates via an Endocytosis- and Proteasome-Independent Pathway

Haiyan Tang,^1,2 Santiago B. Rompani,¹ Joshua B. Atkins,^1,2 Yan Zhou,¹ Thomas Osterwalder,^1, and Weimin Zhong^1,2*

Department of Molecular, Cellular and Developmental Biology,¹ Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut²

Received 7 November 2004/ Returned for modification 20 December 2004/ Accepted 10 January 2005

Numb proteins are evolutionarily conserved signaling molecules that make the daughter cells different after asymmetric divisions by segregating to only one daughter. They contain distinct binding motifs for -adaptin (-Ada) and proteins with Eps15 homology (EH) domains, which regulate endocytosis, and for E3 ubiquitin ligases, which target proteins for proteasome-mediated degradation. In Drosophila melanogaster, Numb acts by inhibiting Notch activity to cause a bias in Notch-mediated cell-cell communication. These findings have led to the hypothesis that Numb modulates Notch signaling by using endocytosis and proteasomes to directly reduce Notch protein levels at the cell surface. Here we show that two Drosophila EH proteins, Eps15 homologue 1 (EH1) and the dynamin-associated 160-kDa protein (Dap160), negatively regulate Notch signaling. However, neither elimination of the binding motifs for endocytic proteins nor simultaneous reduction of proteasome activity affects the activity of Numb proteins. Our findings indicate that an endocytosis- and proteasome-independent pathway may mediate Numb signaling in asymmetric cell fate specification.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: MaTisMed, EMPA, St. Gallen, Switzerland.

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