Associate Professor, The University of Texas MD Anderson Cancer Center
Ph.D., All India Institute for Medical Sciences, New Delhi, 2002
Postdoc, Washington University in St Louis, School of Medicine, 2002-07
RAS/ERK signaling pathways governing germ cell development in C. elegans
A long-term goal of my lab is to understand how one signaling pathway can regulate many distinct biological processes in one tissue. Precise execution of the RAS-Extracellular regulated kinase (ERK) signaling cascade is critical for normal metazoan development, coordinating diverse processes like cell-fate specification, cell survival, and morphogenesis. Inappropriate execution of the RAS-ERK pathway underlies many developmental disorders as well as oncogenesis. ERK is a serine/threonine kinase that executes downstream biological processes via substrate phosphorylation. However, the identity of most ERK substrates remains elusive. Using the model organism Caenorhabditis elegans (C. elegans) and germline development as our biological context, we described at least nine distinct biological processes that are regulated by a single ERK gene, mpk-1. We then identified 30 evolutionarily conserved ERK substrates that regulate at least one of these biological processes. Our studies highlight three key themes that underlie the robustness of RAS-ERK signaling pathway: i) multiple diverse ERK substrates function to control each individual biological process; (ii) different combinations of substrates function to control distinct biological processes; and (iii) regulatory feedback loops between ERK and its substrates help reinforce or attenuate ERK activation. Thus, we have developed a powerful system through which to reveal how ERK regulates a functionally integrated series of biological processes through the coordinate, direct regulation of dozens of molecularly distinct substrates.
Our lab presently focuses on three questions : 1) How does ERK mediated phosphorylation modulate Dicer function and microRNA biogenesis to regulate oocyte to embryo transition and onset of pluripotency? 2) How do ten 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? 3) How does ERK mediated phosphorylation of GSK-3 impact chromatin remodeling machinery to regulate oocyte growth and number?
We fuse technologies such as genetic and RNAi based screening, transgene based analysis, cell biological and microscopic analysis, proteomic methods and large scale sequencing to understand the effect of ERK mediated phosphorylation on each of our target genes and the functional consequence of this phosphorylation to developmental pathways.
As most if not all of the substrates we have identified likely function downstream of ERK in worms, flies, mice and man our studies should generally inform on how the RAS/ERK pathway coordinately regulates many distinct processes in higher metazoans. Our work also has the potential to provide basic insight on the molecular basis through which deregulated ERK activity leads to cancer.
Howell K, Arur S, Schedl T, Sundaram MV (2010) EOR-2 is an obligate binding partner of the BTB-zinc finger protein EOR-1 in Caenorhabditis elegans. Genetics 184:899-913.
Green RA, Kao HL, Audhya A, Arur S, Mayers JR, Fridolfsson HN, Schulman M, Schloissnig S, Niessen S, Laband K, Wang S, Starr DA, Hyman AA, Schedl T, Desai A, Piano F, Gunsalus KC, Oegema K (2011) A high-resolution C. elegans essential gene network based on phenotypic profiling of a complex tissue. Cell 145:470-82.
Arur S, Ohmachi M, Berkseth M, Nayak S, Hansen D, Zarkower D, Schedl T (2011) MPK-1 ERK controls membrane organization in C. elegans oogenesis via a sex-determination module. Developmental Cell 20:677-688.
Yokoo R, Zawadzki KA, Nabeshima K, Drake M, Arur S, Villeneuve AM (2012) COSA-1 reveals robust homeostasis and separable licensing and reinforcement steps governing meiotic crossovers. Cell 149:75-87.
Putty K, Marcus SA, Mittl PR, Bogadi LE, Hunter AM, Arur S, Berg DE, Sethu P, Kalia A (2013) Robustness of Helicobacter pylori infection conferred by context-variable redundancy among cysteine-rich paralogs. PLoS One 8:e59560.
Suen KM, Lin CC, George R, Melo FA, Biggs ER, Ahmed Z, Drake MN, Arur S, Arold ST, Ladbury JE (2013) Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli. Nature Structural and Molecular Biology 20:620-627.
Berkseth M, Ikegami K, Arur S, Lieb JD, Zarkower D (2013) TRA-1 ChIP-seq reveals regulators of sexual differentiation and multilevel feedback in nematode sex determination. Proceedings of the National Academy of Sciences USA 110:16033–16038.
Lopez AL, Chen J, Joo HJ, Drake M, Shidate M, Kseib C, Arur S (2013) DAF-2 and ERK couple nutrient availability to meiotic progression during Caenorhabditis elegans oogenesis. Developmental Cell 27:227-240.
Arur S, Schedl T (2014) Generation and purification of highly specific antibodies for detecting post-translationally modified proteins in vivo. Nature Protocols 9:375-395.
Drake M, Furuta T, Suen KM, Gonzalez G, Liu B, Kalia A, Ladbury JE, Fire AZ, Skeath JB, Arur S (2014) A requirement for ERK-dependent Dicer phosphorylation in coordinating oocyte-to-embryo transition in C. elegans. Developmental Cell 31:614-628.
Swathi Arur, Ph.D.
The University of Texas MD Anderson Cancer Center
Department of Genetics Unit 1010
1515 Holcombe Blvd., Rm. S11.8116A
Houston, Texas 77030, U.S.A.
Tel: (713) 745-8424