Arur Laboratory
Our long-term goal is to understand the exquisite control mediated by a complex signaling pathway in regulating normal development. An ability to understand the mechanisms and principles governing organization of cells and tissues into stereotypical patterns is fundamental to answering the question: what leads to the onset of disease pathology?
Current Research
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. We find that 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. We also find 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.
Unraveling in a systematic way how each of these cellular processes are regulated by ERK in extracellular regulated events will not only provide new insight into how ERK signaling is governed downstream to ERK, but it will also allow us to understand the role of this key pathway in multiple developmental disorders and oncogenesis, where the downstream ERK substrates likely are key drivers of the cellular processes.
We have identified 30 evolutionarily conserved substrates of ERK, and we have revealed that each substrate acts in at least one erk-dependent process in the germline. These effectors derive from many functionally distinct classes of proteins, and our studies highlight three key themes that underlie the robustness of RAS/ERK signaling pathway:
- ERK often regulates multiple functionally diverse targets to govern a given cellular process.
- Individual ERK targets often act in multiple mpk-1 dependent cellular processes.
- Multiple distinct feedback loops exist between ERK and its targets, which function to reinforce or attenuate ERK, signal strength.
Two key questions that emerge from this work are – how does active ERK weave together multiple diverse substrates functioning in distinct spatially overlapping and sequential, biological processes to result in a coordinated and perfectly synchronized developmental outcome(s)? Is execution of ERK signaling evolutionarily conserved at the molecular and cellular level?
Projects in the lab will focus on one effector at a time to understand the role of phosphorylation on each substrate on distinct cellular / molecular events.To this end, we will use genomic, proteomic, genetic, molecular and cell biological analysis, when and where necessary to dissect the molecular mechanisms underlying how cellular events such as germ cell apoptosis, membrane remodeling, size of a single cell: such as an oocyte are each regulated in vivo.