How are signals in a rapidly dividing embryo or tissue functionally integrated to generate pattern? What can we learn from such fundamental processes to inform us more about disease and enhance human health? The manipulation of embryonic tissues has proven to be an extremely powerful tool to decipher the unknowns of cell communication. In this age, understanding the components of a pathway is key to developing targeted therapies that fight human diseases. The long-term goal of my lab is to investigate cellular strategies for signal transduction, integration, and cell fate decision-making using Drosophila melanogaster as an experimental model. Two signaling cascades are of particular interest, the bone morphogenetic protein (BMP) and Wingless (Wg, the Drosophila homolog of Wnt) pathways. Both signaling cascades regulate a diverse range of cellular events such as stem cell maintenance, cell differentiation and organogenesis, while dysfunctional signaling of either pathway can result in human diseases such as cancer. Much remains to be understood about crosstalk events between BMP and Wg, highlighted by our recent biochemical and genetic findings that both pathways compete for the same transcription factor, Mad. We demonstrated that Mad, a known BMP transcription factor, is also required for Wg signaling and the choice between either pathway is determined by its phosphorylation state. This creative discovery has eluded detection until now. Based on our premise of component sharing, this finding suggests that a new complexity between BMP and Wg crosstalk exists, highlighting a further consideration in possible future drug design against either pathway;as targeting one pathway to treat a disease could unintentionally modify the signaling output of the other pathway. The basis of this proposal is to investigate how Mad phosphorylations control its signal choice and duration. We hypothesize that linker phosphorylation of Mad acts as a code for E3-ligase binding and termination of Wg signaling.
Aim 1 wil investigate the role of Mad during Wg signaling.
This aim will be performed using a number of creative research strategies.
Aim 2 will test the hypothesis that phosphorylation of MadS212 is a code for Wg signal termination? Preliminary data suggests that nuclear accumulated Mad is phosphorylated at serine 212 (MadS212) in Wg signaling cells. We will investigate if this phosphorylation event initiates a biological mechanism to terminate Wg signals. The posed question in Aim 3: Is pMadS212 required for BMP signaling? We will address if Mad linker phosphorylations control BMP transcriptional activity differently between Drosophila and mammals. We envisage that this unique competitive relationship between BMP and Wg signaling will help us decipher our broad hypothesis pathway inhibition through component sharing, controlled via phosphorylations. We anticipate this proposal will contribute to the fields of development and cell signaling. In principle, by better understanding signaling processes, new strategies can be developed to protect and improve human health.
We propose to investigate how two signaling pathways, BMP and Wg are integrated in a cell. Both pathways activate their individual signaling cascades to regulate a diverse range of biological events such as stem cell maintenance, cell differentiation and organogenesis, while dysfunctional signaling can lead to diseases such as cancer, thus knowing the components of each pathway is key to combating disease with targeted therapies. The overall aim of this proposal is to investigate how a cell reads a phospho-serine code on Mad, a BMP transcription factor, to establish its signaling preference, BMP or Wg.
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|Aleman, Abigail; Rios, Marlyn; Juarez, Matthew et al. (2014) Mad linker phosphorylations control the intensity and range of the BMP-activity gradient in developing Drosophila tissues. Sci Rep 4:6927|