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Human Molecular Genetics Advance Access published online on August 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl225
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received May 19, 2006
Revised August 5, 2006
Accepted August 5, 2006

Article

Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase

Lawrence T. Reiter 1, Tiffany N. Seagroves 2, Megan Bowers 1, and Ethan Bier 1 *

1 Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Dr., Bonner Hall Room 4221, La Jolla, CA 92093
2 Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Dr., Bonner Hall Room 4221, La Jolla, CA 92093; Department of Pathology, University of Tennessee Health Science Center, 855 Monroe Ave., Memphis, TN 38163

* To whom correspondence should be addressed.
Ethan Bier, E-mail: ebier{at}ucsd.edu


  Abstract

We applied genetic tools available in Drosophila to identify candidate substrates of the UBE3A ubiquitin ligase, the gene responsible for Angelman syndrome (AS). Human UBE3A was expressed in Drosophila heads to identify proteins differentially regulated in UBE3A-expressing versus wild type extracts. Using 2D gel and Maldi-TOF analysis we detected 20 proteins that were differentially regulated by over-expression of human UBE3A in the Drosophila brain. One protein responsive to UBE3A was the Rho-GEF pebble (pbl). Here we present three lines of evidence suggesting that UBE3A regulates Pbl. First, we show genetic evidence that UBE3A and the Drosophila de-ubiquitinase Fat Facets (Faf) exert opposing effects on Pbl function. Second, we find that both Pbl and ECT2, the mammalian orthologue of Pbl called epithelial cell transforming sequence 2 oncogene, physically interact with their respective ubiquitin E3 ligases. Finally, we show that Ect2 expression is regulated by Ube3a in mouse neurons as the pattern of Ect2 expression is dramatically altered in the hippocampus and cerebellum of Ube3a null mice. These results suggest that an orthologous UBE3A post-translational regulatory pathway regulates neuronal outgrowth in the mammalian brain and that dysregulation of this pathway may result in neurological phenotypes including Angelman syndrome and possibly other autism spectrum disorders.


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