2008 Brain Star Award Recipient - Lara Skwarek
Recipient
Lara Skwarek - Biosketch
PhD
University of Toronto
Article
Skwarek L.C., Garroni M.K., Commisso C., and Boulianne G.L. Neuralized contains a phosphoinositide-binding motif required downstream of ubiquitination for Delta endocytosis and Notch signaling. Developmental Cell 2007;13: 783-795.
Significance of the paper
The Notch signalling pathway plays an essential role in cell fate decisions during Drosophila neural development. Since its original identification, Notch signalling has been shown to regulate numerous cell fate decisions in virtually all species. While much is known about the mechanisms regulating signalling downstream of the Notch receptor, little is known about the mechanisms that initiate the signal in the signal sending cell.
Ligand endocytosis is required in the signalling cell for signal initiation and requires the ubiquitin ligase, Neuralized. We have identified an interaction between Drosophila Neuralized and phosphoinositides, modified lipids that mediate membrane trafficking and signalling. Our study is the first to identify direct interactions between phosphoinositides and a protein directly involved in sending the Notch signal and we demonstrate that this interaction has an essential role in the signalling process. This information is important for multiple reasons. We have identified a conserved interaction that may be of general importance for Notch signalling. We have established a direct link between lipid metabolism and Notch signalling, and added another item to the growing list of processes regulated by phospholipids. We have added to our understanding of Neuralized function, and revealed that it likely plays an additional role in ligand endocytosis beyond ligand ubiquitination. Lastly, we have uncovered a new mechanism through which the cell regulates Notch signalling.
Given the importance of Notch signalling to development, and the contribution that aberrations in signalling make to cancer and diseases of the nervous system, expanding our understanding of the cellular basis of Notch signalling is essential to our understanding of how this important pathway functions.