UVM Theses and Dissertations
Format:
Print
Author:
Bior, Bior Kwer
Dept./Program:
Biology
Year:
2013
Degree:
PhD
Abstract:
Adaptor proteins regulate signaling cascades by engaging multiple protein complexes that play indispensable roles in ensuring a precise and speedy transduction of cell signaling events. The ability of adaptor proteins to carry out their diverse functions is subject to a myriad of regulatory mechanisms such as post-translational modifications and protein-protein interactions. This work extends our understanding of signal transduction roles played by the CIN85 scaffolding protein in neuronal and non-neuronal cells. We have characterized a novel phosphorylation-dependent interaction of CIN85 with disabled-1 (Dab1). We have shown that Dab1 inhibits CIN85 phosphorylation on Ser587 in a dose-dependent manner. Also, mimicking phosphorylation of CIN85 at Ser587 results in reduced CIN85-Dabl complex formation in cultured mammalian cells.
This phosphorylation-regulated CIN85 interaction is a phenomenon that is not shared with all CIN85 binding proteins since we show ASAPl and CapZ bind to CIN85 irrespective of the state of Ser587 phosphorylation. Since Dabl is degraded downstream of Reelin signaling during mammalian brain development, our results suggest that Reelin could modulate CIN85 phosphorylation on Ser587 through Dab1 degradation. They also highlight a possibility that CIN85 phosphorylation could be important downstream of ReeIin signaling. To extend our understanding of CIN85 function in neuronal systems, we identified CIN85 binding proteins from murine brain.
The identified proteins are involved in synaptic functions, suggesting that CIN85 could playa role downstream in synaptic transmission, which intriguingly has recently been linked to Reelin signaling in post-natal brain as well as in embryonic brain. To extend our understanding of CIN85 signaling generally, we identified potential CIN85 hinaing proteins in cultured nonneuronal mammalian cells. Some of the identified proteins are involved in cell signaling events such as cytoskeleton rearrangement. The findings presented in this dissertation provide evidence for a role of CIN85 in regulating Dahl as well as provide an important starting point for more focused research aimed at understanding fully CIN85 signaling in mammalian cells.
This phosphorylation-regulated CIN85 interaction is a phenomenon that is not shared with all CIN85 binding proteins since we show ASAPl and CapZ bind to CIN85 irrespective of the state of Ser587 phosphorylation. Since Dabl is degraded downstream of Reelin signaling during mammalian brain development, our results suggest that Reelin could modulate CIN85 phosphorylation on Ser587 through Dab1 degradation. They also highlight a possibility that CIN85 phosphorylation could be important downstream of ReeIin signaling. To extend our understanding of CIN85 function in neuronal systems, we identified CIN85 binding proteins from murine brain.
The identified proteins are involved in synaptic functions, suggesting that CIN85 could playa role downstream in synaptic transmission, which intriguingly has recently been linked to Reelin signaling in post-natal brain as well as in embryonic brain. To extend our understanding of CIN85 signaling generally, we identified potential CIN85 hinaing proteins in cultured nonneuronal mammalian cells. Some of the identified proteins are involved in cell signaling events such as cytoskeleton rearrangement. The findings presented in this dissertation provide evidence for a role of CIN85 in regulating Dahl as well as provide an important starting point for more focused research aimed at understanding fully CIN85 signaling in mammalian cells.