Role of Sec7 Domain Guanine Nucleotide Exchange Factors in Membrane Traffic

University Of Alabama At Birmingham, Birmingham AL

Investigators

Abstract

All cellular life requires membrane traffic. In multicellular organisms, membrane traffic is required for the deposition of the extracellular matrix and cell adhesion, the release and uptake of growth factors and nutrients, and surface signaling and stimulus reception, processes that integrate the developmental and physiological responses of tissues and organs. Understanding the regulatory mechanisms that govern membrane flow provides an essential framework for understanding cellular dysfunction in disease. A family of small GTPases called the ADP-ribosylation factors (ARFs) controls key aspects of membrane traffic by nucleating coating complexes during formation of transport vesicles. The proper function of ARFs in membrane traffic requires their activation. The ARFs are activated by a family of guanine nucleotide exchange factors (GEFs). These GEFs act upstream of ARFs to intercept and then translate internal and external cues into ARF activation. Therefore, understanding GEF function is essential for understanding how ARFs are activated and how membrane traffic is regulated. The investigators aim to characterize three aspects of GEF regulation. First, they will define how GEFs target to subcellular compartments. The intracellular localization of a GEF is critical since it defines the site of ARF activation and spatially restricts the ensuing effector cascade. Second, they will define how the domain structure of GEFs correlates with their function. Third, they will identify external and internal signals that modulate GEF activity. This project impacts broadly on education, scientific equity, inter-disciplinary synergy and scientific infrastructure. These studies will promote the training of undergraduate and graduate students and post-doctoral fellows, with emphasis on training members of underrepresented groups. The project interfaces with physics and mathematics to develop models of biological processes. The project will contribute to professional education, increase representation of minorities in sciences, promote inter-disciplinary research, and develop reagents and resources important to the membrane trafficking field.