Article

Functional Analysis of the NHR2 Domain Indicates that Oligomerization of Neuralized Regulates Ubiquitination and Endocytosis of Delta during Notch Signaling

The Hospital for Sick Children, Program in Developmental and Stem Cell Biology, Toronto, Ontario M5G1X8, Canada.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2012; 32(24). DOI: 10.1128/MCB.00711-12
Source: PubMed

ABSTRACT

The Notch pathway plays an integral role in development by regulating cell fate in a wide variety of multicellular organisms.
A critical step in the activation of Notch signaling is the endocytosis of the Notch ligands Delta and Serrate. Ligand endocytosis
is regulated by one of two E3 ubiquitin ligases, Neuralized (Neur) or Mind bomb. Neur is comprised of a C-terminal RING domain,
which is required for Delta ubiquitination, and two Neur homology repeat (NHR) domains. We have previously shown that the
NHR1 domain is required for Delta trafficking. Here we show that the NHR1 domain also affects the binding and internalization
of Serrate. Furthermore, we show that the NHR2 domain is required for Neur function and that a point mutation in the NHR2
domain (Gly430) abolishes Neur ubiquitination activity and affects ligand internalization. Finally, we provide evidence that
Neur can form oligomers in both cultured cells and fly tissues, which regulate Neur activity and, by extension, ligand internalization.

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    ABSTRACT: As neural stem cells differentiate into neurons during neurogenesis, the proteome of the cells is restructured by de novo expression and selective removal of regulatory proteins. The control of neurogenesis at the level of gene regulation is well documented and the regulation of protein abundance through protein degradation via the Ubiquitin/26S proteasome pathway is a rapidly developing field. This review describes our current understanding of role of the proteasome pathway in neurogenesis. Collectively, the studies show that targeted protein degradation is an important regulatory mechanism in the generation of new neurons. © 2014 Wiley Periodicals, Inc.
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