The Mitogen Activated Protein Kinase (MAPK) signaling pathway is a critical regulator of cellular processes in adult and developing tissues. Deregulated MAPK signaling is associated with a number of diseases, which makes it a key drug target in multiple therapeutic areas. Given a large number of components and levels of regulation within this important pathway, understanding and controlling its function is essentially impossible without quantitative experiments, mathematical modeling, and computational analysis. The terminal patterning system in the early Drosophila embryo is ideally suited for this purpose because of its relative anatomical simplicity and the availability of a large number of genetic tools for the manipulation of MAPK regulators and substrates. We have developed quantitative assays for the in vivo analysis of MAPK phosphorylation and signaling in the terminal patterning system. Based on these assays, in our recently published work we formulated a model according to which the spatial pattern of MAPK signaling in the early embryo is controlled by an enzyme-substrate competition network. Specifically, we proposed that MAPK substrates compete among themselves and with the MAPK phosphatase for binding to the activated MAPK. In addition, we proposed that MAPK substrate competition influences not only the MAPK pathway, but also its interaction with other signaling systems. The work described in this application will provide molecular and functional characterization of the substrate competition mechanism. The main innovation of our proposal is in synthesizing modeling, genetic, and biochemical approaches to developmental signal transduction. By combining our strengths in modeling, genetics, and biochemistry, we are uniquely positioned to formulate and experimentally test systems-level descriptions of MAPK signaling. Going beyond the early Drosophila embryo and MAPK pathway, we propose that substrate competition provides a general signal integration strategy in biomolecular networks where enzymes, such as MAPK, interact with their multiple regulators and substrates.

Public Health Relevance

The MAPK signaling pathway regulates cell growth and differentiation, but deregulated MAPK signaling can lead to a number of human diseases, including cancer. By studying the quantitative principles of the MAPK regulation in development, we expect to gain insights into the design of rational MAPK-directed therapies in diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM086537-04
Application #
8725184
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Hoodbhoy, Tanya
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Princeton University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Princeton
State
NJ
Country
United States
Zip Code
08543
Levario, Thomas J; Zhao, Charles; Rouse, Tel et al. (2016) An integrated platform for large-scale data collection and precise perturbation of live Drosophila embryos. Sci Rep 6:21366
Yang, Liu; Paul, Sayantanee; Trieu, Kenneth G et al. (2016) Minibrain and Wings apart control organ growth and tissue patterning through down-regulation of Capicua. Proc Natl Acad Sci U S A 113:10583-8
Rubinstein, Boris Y; Mattingly, Henry H; Berezhkovskii, Alexander M et al. (2016) Long-term dynamics of multisite phosphorylation. Mol Biol Cell 27:2331-40
Futran, Alan S; Kyin, Saw; Shvartsman, Stanislav Y et al. (2015) Mapping the binding interface of ERK and transcriptional repressor Capicua using photocrosslinking. Proc Natl Acad Sci U S A 112:8590-5
Forés, Marta; Ajuria, Leiore; Samper, Núria et al. (2015) Origins of context-dependent gene repression by capicua. PLoS Genet 11:e1004902
Lim, Bomyi; Dsilva, Carmeline J; Levario, Thomas J et al. (2015) Dynamics of Inductive ERK Signaling in the Drosophila Embryo. Curr Biol 25:1784-90
Jindal, Granton A; Goyal, Yogesh; Burdine, Rebecca D et al. (2015) RASopathies: unraveling mechanisms with animal models. Dis Model Mech 8:769-82
Mattingly, Henry H; Chen, Jessica J; Arur, Swathi et al. (2015) A Transport Model for Estimating the Time Course of ERK Activation in the C. elegans Germline. Biophys J 109:2436-45
Dsilva, Carmeline J; Lim, Bomyi; Lu, Hang et al. (2015) Temporal ordering and registration of images in studies of developmental dynamics. Development 142:1717-24
Berezhkovskii, Alexander M; Shvartsman, Stanislav Y (2014) On the GFP-based analysis of dynamic concentration profiles. Biophys J 106:L13-5

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