Proteases comprise more than 2 percent of the known proteome, with the family of serine proteases constituting one of the largest protease families. The trypsin-like serine proteases long have been recognized to be critical effectors of biological processes as diverse as digestion, blood coagulation, fibrinolysis and immunity.
The complete sequencing of several vertebrate genomes at the turn of the millennium unexpectedly revealed a new group of serine proteases that are structurally distinct and anchored directly to the plasma membrane. These enzymes, broadly termed the membrane-anchored serine proteases, are synthesized with amino- or carboxy-terminal extensions that serve to anchor their serine protease catalytic domains (see Hooper et al, Bugge et al and Szabo and Bugge).
Since the emergence of this subfamily, researchers have begun to investigate the biochemical and physiological activities of these enzymes and have come up with some surprising results. The 2013 American Society for Biochemistry and Molecular Biology special symposium on membrane-anchored serine proteases, held in September in Potomac, Md., brought many of these researchers together for the first time, revealing that while there are structural and phylogenetic commonalities among these enzymes, there are also stark differences in biological function.
The conference opened with a keynote lecture from Qingyu Wu (Lerner Research Institute, The Cleveland Clinic) titled “The membrane serine protease corin: from physiology to pathology.” This enthusiastic and entertaining talk focused on a journey of discovery into corin biology, physiology and pathways to the clinic. It was an inspiring start to the conference.
Talks covering wide-ranging combinations of biochemical analyses, animal models and human studies were presented, revealing that the membrane-anchored serine proteases are key pericellular contributors to processes vital for development and the maintenance of homeostasis. They regulate diverse fundamental biological processes including epithelial barrier function, water transport, iron homeostasis, blood-pressure regulation, hearing, fertilization and embryonic development. Their misuse in many cellular contexts contributes to human illnesses including cardiovascular disease, cancer and viral infection.
Several attending researchers have focused on the identification of target substrates for the membrane-anchored serine proteases and the regulation of their protease activities; however, as the meeting progressed it became clear that the biology is not as simple as first thought. Endogenous protein substrates targeted by membrane-anchored serine proteases include peptide hormones, growth and differentiation factors, receptors, enzymes, adhesion molecules and viral coat proteins.
A significant research focus of several groups is the regulation and activities of the epithelial type II membrane-anchored serine protease called matriptase. The serine proteases share a common catalytic mechanism for selective cleavage of specific substrates and frequently are involved in consecutive proteolytic reactions or protease cascades, where one protease precursor or zymogen is the substrate for an active protease. Provocative new data relating to the matriptase pathway was presented at the meeting suggesting that membrane-anchored serine proteases may serve as nonenzymatic, allosteric co-factors for activation of other protease zymogens.
Several studies presented indicate that these enzymes are interconnected with known zymogen activation cascades at the cell surface, including the coagulation and fibrinolytic cascades. Furthermore, there is evidence that proteases within this family can constitute a cell-surface proteolytic cascade within themselves and act upstream of effector proteases, providing the capacity for unleashing a burst of proteolytic potential. Several of the membrane-anchored proteases, such as matriptase and testisin, are capable of activating G-protein–coupled receptors, such as protease-activated receptor type 2, and receptor tyrosine kinase ligands, such as pro-hepatocyte growth factor, on the surface of different cell types, thus potentially constituting a so-called missing link from the extracellular protease cascades to intracellular signaling pathways.
We had an outstanding selection of junior investigators present their research results in the oral sessions, indicating that this is a young field that will remain vibrant for many years to come. Participants came from U.S. and international laboratories and included researchers from academic institutions, government and industry. The meeting had an encouraging and informal atmosphere, which undoubtedly fostered collaborative interactions among the researchers. The poster session also attracted a lot of interest. It was a challenging and rewarding experience and provided some thought-provoking suggestions for future research.
Overall, the meeting was entertaining, interactive and motivating while covering a variety of areas in the emerging field of membrane-anchored serine proteases. The challenges ahead include the development of unique tools with which to study these enzymes to show how these proteases are used and modulated by the cell and how they can be exploited for therapeutic benefit.
Toni M. Antalis (email@example.com) is a professor at the University of Maryland School of Medicine. Thomas H. Bugge (firstname.lastname@example.org) is a senior investigator at the National Institute of Dental and Craniofacial Research.