BMP signaling has been found to be critically involved in a multitude of biological processes from embryonic tissue specification at the beginning of an organism?s life, to maintenance of tissue homeostasis in the adult. The significance of this signaling cascade in human physiology is most evident in the array of diseases associated with aberrant BMP signaling, these include cancer, pathologies of connective tissues and cardiovascular diseases, all of which have serious consequences on human health and development. Even with our growing knowledge of this signaling pathway during development and disease, there are still many unanswered questions that continue to drive research in this field. Broadly, our goal is investigate how BMP signals in rapidly dividing embryonic tissues are fine-tuned at the level of Mad linker phosphorylations (Mad is the transcription factor which transduces the BMP signal). In preliminary data obtained from Drosophila tissues we found linker phosphorylated Mad localized to sub-cellular punctate structures, which appeared prominently when nuclear phosphorylated Mad levels began to decrease. Interestingly, phosphorylated Mad puncta appear to co-localize with endocytosed type 1 BMP receptors. Based on our preliminary data we propose a role for linker phospho- Mad in directing endocytosed type 1 BMP receptors for degradation. The prevailing view of linker phospho- Mad is that it targets BMP-activated Mad for degradation, but how endocytosed type 1 receptors are directed to the lysosome or proteasome for degradation is still a very much debated issue. The two aims we plan to investigate are:
Aim 1, investigating the origin or linker phosphorylated Mad puncta and Aim 2, does linker phosphorylated Mad regulate type 1 BMP receptor turnover. We propose a combination of Drosophila genetics and immunofluorescence experiments to generate robust data to test our hypothesis. Overall, the BMP pathway is highly conserved throughout the animal kingdom, even down to the specific Mad phosphorylation sites of interest, which allows us to utilize the genetically amenable and rapidly developing fruit fly (Drosophila melanogaster) to test our hypothesis. In conclusion, any new findings we make using Drosophila will have direct implications for our understanding of how the human BMP pathway operates, with particular relevance to its role in development and disease.
The Bone Morphogenetic Protein (BMP) signaling pathway has been found to be critically important during embryonic development and tissue homeostasis, while dysfunctional signaling has been associated with many human diseases such as cancer. To understand how this signaling pathway is responsible for a vast array of biological actions, it is critical to identify how it?s regulated. In this project, we will exploit the advantages of a genetically amenable model organism to study BMP pathway regulation at the level of its transcription factor Mad.
