Actin regulation of CD36 receptor organization and signaling

The goal of this project is to deepen our understanding of how cells regulate the process of sensing and responding to their environment. This will be achieved by investigating the interplay between cell surface proteins, called receptors, which allow cells to sense and respond to their environment, and the actin cortex, a component of the cell skeleton that is subjacent to the cell surface and that is a major regulator of cell surface receptors.

The research will take one particular receptor, called CD36, as a model system, as it is likely representative of many cell surface receptors that are influenced by the actin cortex without directly binding to it. Using novel integrative microscopy and computational analysis tools, the investigator’s research team will (i) quantitatively characterize the influence of the actin cortex on nearby cell surface receptor behavior, (ii) shed light on the molecular mechanisms underlying this influence, and (iii) investigate how this influence may render receptor function sensitive to the stiffness of the cell’s environment, because of the sensitivity of the actin cortex to environmental stiffness.

Through participation in the described research, as well as through a companion entry-level summer course on computational image analysis for undergraduate students, this project will train graduate, undergraduate and high school students in cutting-edge quantitative microscopy, an increasingly critical technique for modern biological research.

CD36 is an integral membrane protein that is expressed on the surface of many cell types and that binds diverse ligands. As for many receptors, CD36 signaling requires clustering, for which the actin cytoskeleton plays an important role. However, there still is a lack of mechanistic and quantitative understanding of how the actin cytoskeleton, and in particular the actin cortex, regulates the organization and signaling of cell surface receptors.

To fill this gap, this project will pursue three specific aims: (i) Determine the influence of the actin cortex on CD36 signaling through a quantitative understanding of its influence on cell surface CD36 organization. (ii) Test the hypothesis that integrins and tetraspanins form the molecular link between cell surface CD36 and the actin cortex. (iii) Test the hypothesis that the actin cortex mediates crosstalk between microenvironmental stiffness and CD36 signaling. For this, the investigator’s research team will employ a novel approach combining simultaneous high spatiotemporal resolution imaging of cell surface receptors and cortical actin in live cells with statistical analysis of the relationships between them, as well as mutagenesis of CD36 and exposure of cells to microenvironments of different stiffness.

Altogether, these studies will help reveal general principles of the mechanisms and signaling consequences of actin-mediated cell surface receptor organization.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.