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.
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.
| Patel, Aleena L; Shvartsman, Stanislav Y (2018) Outstanding questions in developmental ERK signaling. Development 145: |
| Jindal, Granton A; Goyal, Yogesh; Yamaya, Kei et al. (2017) In vivo severity ranking of Ras pathway mutations associated with developmental disorders. Proc Natl Acad Sci U S A 114:510-515 |
| Song, Yonghyun; Marmion, Robert A; Park, Junyoung O et al. (2017) Dynamic Control of dNTP Synthesis in Early Embryos. Dev Cell 42:301-308.e3 |
| Goyal, Yogesh; Jindal, Granton A; Pelliccia, José L et al. (2017) Divergent effects of intrinsically active MEK variants on developmental Ras signaling. Nat Genet 49:465-469 |
| Johnson, Heath E; Goyal, Yogesh; Pannucci, Nicole L et al. (2017) The Spatiotemporal Limits of Developmental Erk Signaling. Dev Cell 40:185-192 |
| Rogers, William A; Goyal, Yogesh; Yamaya, Kei et al. (2017) Uncoupling neurogenic gene networks in the Drosophila embryo. Genes Dev 31:634-638 |
| Lim, Bomyi; Dsilva, Carmeline J; Kevrekidis, Ioannis G et al. (2017) Reconstructing ERK Signaling in the Drosophila Embryo from Fixed Images. Methods Mol Biol 1487:337-351 |
| Grossman, Rona; Paroush, Ze'ev (2017) High-Throughput In Vitro Identification of Direct MAPK/Erk Substrates. Methods Mol Biol 1487:127-135 |
| Jindal, Granton A; Goyal, Yogesh; Humphreys, John M et al. (2017) How activating mutations affect MEK1 regulation and function. J Biol Chem 292:18814-18820 |
| Grant, Meagan G; Patterson, Victoria L; Grimes, Daniel T et al. (2017) Modeling Syndromic Congenital Heart Defects in Zebrafish. Curr Top Dev Biol 124:1-40 |
Showing the most recent 10 out of 30 publications
