Cell signaling determines cellular behavior through the regulation of complex biochemical networks, slight disruptions in which can lead to a plethora of pathologies. The key to curing such diseases lies in part in gaining a comprehensive understanding of the mechanisms and molecules involved. The aim of this thesis was to characterize the role of A Kinase Anchoring Protein 200 (AKAP200), to expand our current understanding of signaling pathways in the context of development. AKAP200, a scaffolding protein previously known for its role in the spatial and temporal regulation of Protein Kinase A (PKA), was identified in our laboratory in a dominant modifier screen as a novel regulator of Planar Cell Polarity (PCP), which refers to the polarization of cells across the plane of an epithelium.
Here, I demonstrate a novel role of AKAP200 in promoting Notch protein stability. In Drosophila, AKAP200 mutants show phenotypes that resemble Notch loss-of-function defects, including eye patterning and sensory organ specification defects, and its overexpression affects wing venation. Importantly, Notch signaling is downstream of the PCP pathway in the eye, the context, where AKAP200 was identified. AKAP200 shows a strong genetic interaction with Notch in the eye and thorax, and appears to promote Notch activity. Interestingly, these interactions are independent of AKAP200's role in PKA signaling, linking AKAP200 to other functions. AKAP200 physically interacts with Notch, stabilizes endogenous Notch protein, and limits its ubiquitination. I provide genetic and molecular evidence that AKAP200 protects Notch from the E3-ubiquitin ligase Cbl and the lysosomal pathway, thereby promoting Notch signaling. In this thesis, I have discovered a novel role of AKAP200 as a post-translational regulator of Notch signaling that functions to achieve optimal Notch protein levels.
|Commitee:||Kalderon, Daniel, Krauss, Robert, O'Connell, Matthew, Pfleger, Cathie|
|School:||Icahn School of Medicine at Mount Sinai|
|Department:||Developmental and Stem Cell Biology|
|School Location:||United States -- New York|
|Source:||DAI-B 79/02(E), Dissertation Abstracts International|
|Keywords:||Drosophila, Lysosome, Notch signaling, Protein stability, Ubiquitination|
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