Research:

The development and maintenance of multicellular organisms rely on central processes such as cell division, migration and differentiation. These basic cellular activities are governed and coordinated by a system of communications - cellular signaling. Errors in transmission of signals through the complex signaling networks have serious consequences, including tumor formation or developmental diseases. The major focus of our research is to decipher cellular machineries that control accurate signal transmission in space and time.

Our current focus is the canonical Extracellular signal-Regulated Kinases 1 and 2 (ERK1/2) signaling pathway. This pathway is well known for its essential role in several critical steps of embryonic development and tumor progression, and kinases and phosphatases of this pathway have been extensively studied and targeted therapeutically.
(Figure 1)
However, the mechanisms that determine the signal specificity and orchestrate the diverse biological outcomes of ERK1/2 signaling are still poorly understood. Critical players within this pathway that arbitrate specificity of signaling events are scaffold proteins. Scaffolds bring signaling partners to close proximity and help to move signaling complexes to particular cellular locations. We aim to elucidate the mechanisms by which signaling scaffolds orchestrate the regulation of signaling in time and spaces as well as the role scaffolds play in progression of disease.

One such critical player is the signaling scaffold protein Shoc2. Shoc2 functions as a platform that holds several signaling partners together therefore allowing efficient signal transmission. Mutations in Shoc2 cause Noonan-like syndrome, a developmental disorder that is predominantly caused by the dysregulation of RAS signaling through the ERK1/2 cascade (e.i. RASopathy ). Moreover, Shoc2-mediated ERK1/2 signals are of critical importance in cancerogenesis .

  • Our goal is to define the machinery that Shoc2 assembles to avoid errors of excessive or insufficient signal transmission. We have already identified that proteins of the ubiquitin proteasomal system and endo-cellular trafficking machineries play a major role in monitoring signaling events transduced by Shoc2.
    (Figure 2)
    This project is in progress, and we continue building this multi-protein assembly.

  • We also use zebrafish as small organism models to elucidate the role Shoc2 plays in embryonic development and to decipher the signaling events mediated through the Shoc2 scaffold. This exciting model allows us to have a very unique window into the very early stages of embryonic development.

  • Knowing the critical role of Shoc2 in cancerogenesis , understanding its contributions to these pathologies is one of our priorities as well.

To provide a detailed understanding of how Shoc2 is involved in progression of developmental diseases and cancerogenesis , we employ a comprehensive array of methods such as state-of-the-art innovative microscopy, genetic, molecular, and cellular techniques.

Ultimately, our research will contribute to the advancement of novel therapeutic strategies for treatment of developmental disorders and cancer progression and potentially will result in improved therapies with low toxicity.

OUR CURRENTLY FUNDED PROJECTS:

  • American Cancer Society (RSG-14-172-01-CSM): "SHOC2 mediates motility signals of the ERK pathway"
  • National Institutes of Health/NIGMS (1R01GM113087): "Deciphering the molecular mechanisms underlying active scaffolding"