Grants and Contracts Details

Description

The overall goals of our NIGMS-supported program have been to address the fundamental molecular mechanisms of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signal transmission guided by the Shoc2 scaffold in normal physiology and disease. Our efforts have led to the discovery that the ubiquitin machinery regulates the signal transmission of ERK1/2 signals through the Shoc2 scaffolding module and controls assembly of the proteins in the complex. We identified the E3 ligase HUWE1 and AAA+ ATPases VCP and PSMC5 as key components modulating the ability of Shoc2 transmit ERK1/2 signals. We then discovered that localization of Shoc2 to endosomes that is critical for the proper transmission of ERK1/2 signals. This work further revealed a distinct function of the signals transduced by the Shoc2 scaffold in ERK1/2–mediated cell adhesion and motility. Furthermore, we developed a zebrafish model for Shoc2 deficiency and established that loss of Shoc2 has a systemic effect of early development recapitulating congenital malformations observed in patients with Shoc2 mutations. The central premise for the proposed studies is that ubiquitination offers novel mechanisms for the regulation of ERK1/2 biology. A thorough understanding of the mechanism by which key regulators and mediators of the ubiquitin system modify Shoc2-ERK1/2 signaling and trafficking is essential for understanding dysregulated mechanisms in ERK1/2-related diseases and for identifying new drug targets. The proposed studies will allow my research group to gain a thorough understanding of novel concepts that we pioneered - that ubiquitination of Shoc2 regulates signaling in normal physiology and is disrupted in congenital disease. Our studies have raised many exciting questions and the most transformative research will be pursued. ERK1/2 is critical in normal development; however molecular details of Shoc2-activated ERK1/2 signals promote critical early developmental stages are not understood and will be determined. There is also a limited understanding of how endosomal sorting machinery regulates ERK1/2 activity. Thus, we will define the mechanisms by which the endosomal sorting regulates ubiquitin-driven remodeling of the Shoc2 complexes and signaling. The key steps that segregate Shoc2 into the distinct intracellular sorting pathways are not known and will be delineated. Shoc2 mutations cause congenital disease however, it is not clear how Shoc2 signals impact ERK1/2 developmental signals or contribute to cancer progression and will be examined. We are well equipped to perform these studies given my laboratory's experience in delineating molecular mechanisms of Shoc2-mediated signaling and our innovative comprehensive approach encompassing genetic, state-of-the-art microscopy, cell-based and biophysical methodologies. Of note, we will use zebrafish as a vertebrate model to investigate the in vivo effect of Shoc2 gene editing on the early stages of development. Zebrafish offer distinct advantages for studies of development including their transparency, external and rapid development. The proposed research is expected to provide a detailed mechanistic understanding of how Shoc2 is involved in determining the specificity of ERK1/2 signaling outcomes and has the potential for high impact by laying the groundwork for future studies on developmental disorders and contributing to the advancement of novel therapeutic strategies and biomarkers.
StatusActive
Effective start/end date5/1/204/30/25

Funding

  • National Institute of General Medical Sciences: $1,147,440.00

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