Cells are information management machines that must interpret a milieu of extracellular cues to control outputs ranging from proliferation to differentiation and migration. Integrins are ab heterodimeric proteins that link the extracellular matrix (ECM) to the cytoskeleton and control intracellular signaling cascades. While a great deal is known about adhesion and signaling functions for most integrins, signal transduction pathways regulated by integrin avb8, which was discovered more than 20 years ago, remain largely unexplored. avb8 integrin contains several novel features that suggest unique signaling functions. For example, the primary amino acid sequence of the b8 cytoplasmic tail is divergent from other integrins, suggesting interactions with atypical signaling effectors. In addition, b8 integrin lacks an extracellular """"""""deadbolt"""""""" domain that in other integrins modulates inside-out activation, suggesting different mechanisms of ECM affinity regulation. The PI's group has performed genetic screens and proteomic-based experiments to identify intracellular signaling effectors that bind to b8 integrin, but not to other integrin subunits. In this project we will anayze how these effector proteins contribute to avb8 integrin-mediated cell migration using genetically engineered mouse models and primary culture systems.
In Aim 1 we will characterize links between avb8 integrin, the cytoplasmic tyrosine phosphatase PTP-PEST, and the Rho GTPase effector protein RhoGDI1.
In Aim 2 functional interactions between avb8 integrin and Spinophilin, a cytoskeletal scaffolding protein and regulatory subunit of the serine/threonine protein phosphatase 1 (PP1), will be analyzed. Lastly, integrin-dependent links between Spinophilin/PP1, PTP-PEST and Rho signaling will be explored. In summary, experiments in this project will reveal new and important mechanisms underlying avb8 integrin control of cell adhesion and migration in development and disease.
In this project we will use mouse models and primary cell culture systems to study signal transduction pathways regulated by avb8 integrin. An emphasis will be placed on understanding how cell motility is controlled via signaling effectors that bind selectively to the b8 integrin cytoplasmic tail. These results will reveal novel mechanisms that drive cell migration and invasion in development and disease.
