The extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway plays an essential role in several critical steps of embryonic development and tumor progression. It also controls critical cellular functions such as apoptosis, motility and differentiation. Kinases and phosphatases of this pathway have been extensively studied and targeted therapeutically. However, the mechanisms that determine the signal specificity and orchestrate the diverse biological outcomes of ERK1/2 signaling are still poorly understood. Scaffold proteins are key players in the ERK1/2 signaling pathway that are thought to integrate incoming signals and deliver signaling specificity, and yet their role in signal propagation and the mechanisms of their action are still unknown. The long-term goal of our research is to reveal how scaffold proteins are involved in the biological processes regulated by the ERK1/2 cascade. In this way, new therapeutic strategies can be developed to more specifically target this cascade without affecting other essential biological functions. The objective of this proposal is to determine the mechanisms underlying the ability of the key scaffold protein, Shoc2, to regulate ERK1/2-mediated cell motility. Shoc2 is essential for embryonic development and a critical regulator of ERK1/2 activity. We have shown that depletion of Shoc2 in zebrafish results in defects in hematopoiesis. We also found that Shoc2 integrates endocytic and ubiquitin machineries to regulate ERK1/2 signaling. Based on this preliminary data, the central hypothesis of this proposal is that Shoc2 creates a signaling hub that regulates ERK's developmental signals in a spatio-temporal manner. Our hypothesis will be tested by pursuing three specific aims:
Aim 1 will determine the spatio-temporal organization and dynamics of Shoc2 scaffold complexes.
Aim 2 will reveal the molecular mechanism by which the E3 ligase HUWE1 controls Shoc2 function and assembly of the Shoc2 scaffold complexes.
Aim 3 will determine the signaling events mediated through the Shoc2 scaffold complexes that control embryonic development. The proposed Aims therefore are expected to provide a detailed understanding of how Shoc2 is involved in determining the specificity of ERK1/2 signaling outcomes. These studies will employ state-of-the-art innovative microscopy, genetic, molecular, and cellular techniques and will provide critical insights into our understanding of the spatial-temporal control of signaling by scaffold proteins. This research has significance for contributing to the advancement of novel therapeutic strategies and biomarker innovations for developmental disorders and cancer progression. Thus, the proposed studies are relevant to the NIH's mission to increase understanding of biological processes and to lay the foundation for advances in disease diagnosis, treatment and prevention.
PUBLIC HEALTH. Deregulation of the MAPK signaling cascade is found in 30% of all tumors and multiple cardiac abnormalities, and virtually every component of the cascade is target for therapeutic development. The effective targeting of this pathway in disease relies upon a clear understanding of all the intricacies in modulating numerous signaling components. Understanding the molecular mechanisms underlying the role of Shoc2 in MAPK signaling propagation potentially may lead to the development of specific prognostic markers and will enhance the effectiveness of targeted treatment.
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