Roles of the HECT-Type Ubiquitin E3 Ligases of the Nedd4 and WWP Subfamilies in Neuronal Development

by Hung-En Hsia
Doctoral thesis
Date of Examination:2014-10-20
Date of issue:2015-05-21
Advisor:Dr. Hiroshi Kawabe
Referee:Prof. Dr. Nils Brose
Referee:Dr. Judith Stegmüller
Referee:Prof. Dr. Andreas Wodarz
Persistent Address: http://dx.doi.org/10.53846/goediss-5079

 

 

Files in this item

Name:DThesis revised.pdf
Size:7.34Mb
Format:PDF

The following license files are associated with this item:

Abstract

English

Protein ubiquitination is a core regulatory principle in neuronal development. In this study, I used brain specific KO mice to investigate the roles of several HECT-type Nedd4 superfamily E3 ligases, i.e. Nedd4-1, Nedd4-2, WWP1, and WWP2, during brain development. I show that Nedd4-1 and Nedd4-2 are required for neuronal axonal growth and branching in the mouse central nervous system. Previously published data indicated that the lipid phosphatase PTEN may be a relevant substrate of Nedd4-1 and Nedd4-2. However, I show that aberrant PTEN ubiquitination is not involved in the impaired axon growth upon deletion of Nedd4-1 and Nedd4-2. Rather, PTEN limits Nedd4-1 expression at the translational level by modulating the activity of mTORC1, a protein complex that controls protein synthesis and cell growth. I further show that Nedd4-1 is one of the major targets of PTEN- mTORC1 signaling in the control of neurite growth. In addition, I identify the deubiquitinase Usp9x as a binding partner of WWP1 and WWP2. WWP1 and WWP2 may counteract the function of Usp9x by interacting with Nuak1 and Nuak2, protein kinases that can be deubiquitinated and activated by Usp9x. Moreover, I show that Cdk5, a protein kinase with multiple roles in the nervous system, is ubiquitinated by WWP1 and WWP2 in vivo via a K63-linked polyubiquitin chain. Such ubiquitination of Cdk5 by WWP1 and WWP2 may alter Cdk5 activation or subcellular localization and may thus affect multiple cellular processes during brain development.
Keywords: Protein Ubiquitination; Neuronal Development; Nedd4
 
Statistik