Work in the Arur Lab utilizes the nematode Caenorahbditis elegans and germ line development to study ERK signaling. A long-term goal of the lab is to understand how active ERK2 controls and co-ordinates multiple different developmental events in one tissue. Downstream to ERK2, the linear RAS-ERK pathway becomes an intricate network of signaling molecules, with at least 30 direct effectors, each of which functions in its own signaling module to govern an ERK-dependent event. Findings have also shown extensive signal-integration and cross-talk of ERK with other signaling pathways, such as the wnt signaling pathway, the chromatin modification machinery, and the miRNA processing cascade.
Determing in a systematic way how each ERK substrate regulates different biological processes during normal development will a) uncover novel functions of each substrate protein in a specific biological process, and b) also allow us to understand the role of phosphorylation on each substrate in both developmental disorders and oncogenesis, where the downstream ERK substrates likely are key drivers of the disease.
Three key questions our lab focuses on answering are:
1) How does ERK-mediated phosphorylation modulate Dicer function and microRNA biogenesis to regulate oocyte to embryo transition and onset of pluripotency?
In this project, we are combining transgenic, deep sequencing and proteomic methods to understand the mechanism of ERK-mediated regulation on Dicer function.
2) How do 10 of the ERK substrates integrate and cross-talk with each other in the network? What is the function of each substrate in this network, and the impact on other substrates?
This one question is an integration of multiple projects. We have generated phospho-specific antibodies to each of the proteins in the ERK substrate network. Here we use RNAi screens and cell biological methods (with confocal microscopy) to map the localization of each substrate pre- and post-phosphorylation to assess impact of phosphorylation on cellular localization and binding partners in the context of other substrates in that group.
3) How does ERK-mediated phosphorylation of GSK-3 impact chromatin remodeling machinery to regulate oocyte growth and number?
GSK-3 is a known mediator of metabolic signals in response to hormonal signals and oxidative stress. We uncovered a novel role / localization of this protein in response to nutrient availability and ERK activation as a chromatin binding protein that may function as a transcriptional repressor. In this study, we explore the role of GSK-3 to modulate gene expression and chromatin remodeling using various transgenic and ChiP-Sequencing based analyses. We also explore the role of GSK-3 in regulating growth of cells in response to metabolic and oxidative stresses during meiotic development of oocytes.