The type II transmembrane serine proteases are a relatively uncommon family of proteins associated with abnormal epithelial morphogenesis and cellular differentiation, heart and respiratory disorders, and cancer. Because the developmental and clinical importance of these proteases has only recently been appreciated their cellular behaviors are poorly understood. The exception is the Drosophila Stubble type II transmembrane serine protease which regulates the actin cytoskeleton via RhoA signaling during imaginal disc morphogenesis, an unexpected role for a protein with an extracellular proteolytic domain. Two other members of the type II transmembrane serine protease family have been linked to intracellular signaling, suggesting that many or all members of this family may exert their effects through signal transduction networks. We propose to use the Drosophila Stubble protease as a model system to study signaling by a type II transmembrane serine protease family member. The long-term goal is to improve our understanding of the cellular behavior of this important class of proteins. Our preliminary data indicate that RhoA functions downstream of Stubble during leg imaginal disc morphogenesis. We will use a combination of genetic analysis, biochemistry, and cell biology to confirm these findings. We will specifically ask if Stubble regulates actin cytoskeletal dynamics via activation of RhoA signaling leading to phosphorylation of the myosin regulatory light chain, and activation of the heavy chain of non-muscle myosin II. We have also identified mutations in three genes that appear to be involved in a Stubble-RhoA signaling pathway in leg imaginal discs. We will clone these genes to identify their gene products, as a first step toward understanding their roles in this signaling pathway.
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