ERK (extracellular signal regulated kinase) is the terminal kinase of a number of signaling cascades that regulate animal development and is often inappropriately activated in cancer. ERK regulates biological processes through phosphorylation of substrate proteins. However, in most cases the substrates that are phosphorylated for a given biological process are not known and the mechanism by which substrates achieve a biological outcome is unclear. The experimental animal model C. elegans has a single ERK ortholog, MPK-1, which functions in nine different processes that are necessary for germline development. The long-term objectives of this research program are to: 1) identify substrates of MPK-1 and to use germline development in this system to understand substrate function, regulation and regulatory interactions, and 2) determine whether the orthologs of C. elegans MPK-1 substrates are ERK substrates in mammalian systems, focusing on mouse oocyte maturation and Meiosis II (MII) arrest. A three-part functional genomics screen identified 25 MPK-1 substrates, which contain multiple ERK docking sites conserved in position with their mouse/ human orthologs, that function in one or more processes in C. elegans germline development. For a number of the substrates, phospho-specific antibodies were generated to verify MPK-1 dependent phosphorylation in vivo. We propose two lines of follow-up studies. The first is to use the C. elegans germline to understand temporal/spatial aspects of substrate phosphorylation, to understand how phosphorylation affects function and to investigate substrate mediated feedback regulation of MPK-1 activation. The second is to use the phospho-specific antibodies we have generated to test if the orthologs of MPK-1 substrates are ERK substrates in mammalian cell culture and in mouse cumulus enclosed oocytes. ERK functions in a number of processes within mouse oocyte meiotic maturation and MII arrest;the phospho-specific antibodies we have generated may be useful markers for oocyte development and may identify new substrates that act in maturation and MII arrest. Finally, we propose to extend our three-part functional genomic screen to identify new MPK-1 substrates using a different set of initial criteria. ERK is inappropriately activated in cancers where oncogenic mutations have occurred in the upstream signaling cascade members RAF, RAS and receptor tyrosine kinases (e.g. the EGF receptor). Since it is ultimately the substrates that are being inappropriately phosphorylated in these cancers that lead to ERK dependent phenotype, identifying the substrates and uncovering their function, regulation and regulatory consequences is essential part of understanding tumor biology and how it may be treated.

Public Health Relevance

ERK MAP Kinase signaling is important in normal development and occurs inappropriately in many cancers (e.g. colorectal, melanoma, etc). It is the substrates that are phosphorylated by ERK that execute developmental processes and lead to uncontrolled growth and metastasis phenotypes in cancer. Identification of ERK substrates and characterization of their function is thus essential for understanding both normal development and cancer, where the substrates are potential biomarkers for outcome and therapeutic targets for cancer treatment.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Haynes, Susan R
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Washington University
Schools of Medicine
Saint Louis
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Nadarajan, Saravanapriah; Mohideen, Firaz; Tzur, Yonatan B et al. (2016) The MAP kinase pathway coordinates crossover designation with disassembly of synaptonemal complex proteins during meiosis. Elife 5:e12039
Arur, Swathi; Schedl, Tim (2014) Generation and purification of highly specific antibodies for detecting post-translationally modified proteins in vivo. Nat Protoc 9:375-95
Hansen, Dave; Schedl, Tim (2013) Stem cell proliferation versus meiotic fate decision in Caenorhabditis elegans. Adv Exp Med Biol 757:71-99
Pazdernik, Nanette; Schedl, Tim (2013) Introduction to germ cell development in Caenorhabditis elegans. Adv Exp Med Biol 757:1-16
Wang, Qiang; Chi, Maggie M; Schedl, Tim et al. (2012) An intercellular pathway for glucose transport into mouse oocytes. Am J Physiol Endocrinol Metab 302:E1511-8
Luzzo, Kerri M; Wang, Qiang; Purcell, Scott H et al. (2012) High fat diet induced developmental defects in the mouse: oocyte meiotic aneuploidy and fetal growth retardation/brain defects. PLoS One 7:e49217
Wolfner, Mariana F; Schedl, Tim (2012) The 2012 Thomas Hunt Morgan medal: Kathryn V. Anderson. Genetics 191:293-5
Arur, Swathi; Ohmachi, Mitsue; Berkseth, Matt et al. (2011) MPK-1 ERK controls membrane organization in C. elegans oogenesis via a sex-determination module. Dev Cell 20:677-88
Johnston, Mark; Andrews, Brenda J; Hawley, R Scott et al. (2011) G3, GENETICS, and the GSA: Two Journals, One Mission. Genetics 189:1-2
Sengupta, Piali; Schedl, Tim (2011) Cellular reprogramming: chromatin puts on the brake. Curr Biol 21:R157-9

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