Serpin Peptidase Inhibitor, clade F (Serpin F1), also called Pigment Epithelium-Derived Factor (PEDF), EPC-1, and PIG35, is a member of the Serpin superfamily of serine protease inhibitors (1-5). This superfamily is comprised of two protein groups with dissimilar functions. One group demonstrates protease inhibition while proteins in the other group display no protease inhibition, but rather, perform diverse functions, such as molecular chaperones, circulating transporters, and tumor suppressors (2). Serpin F1 is part of this latter group. It is a 50 kDa, monomeric phosphoglycoprotein that is comprised of three beta -sheets, 8-10 alpha -helices, and a C-terminal reactive center loop (RCL), a structure common to all Serpins (2-5). However, unlike Serpins that exhibit protease inhibiting activity, the RCL of Serpin F1 does not undergo a conformational change, a prerequisite for anti-protease activity (3, 5). Such cleavage does, however, generate a 46 kDa fragment that possesses nonprotease-associated bioactivity (6). Mouse Serpin F1 displays 88% and 93% amino acid sequence identity with the human and rat orthologs, respectively.
Serpin F1 is a multifunctional protein that is synthesized by multiple cell types and is expressed in many tissues including the retinal pigment epithelium, liver, bone, connective, heart, and adipose tissues (1, 3, 5, 7, 8). It has been shown to bind to several different cell surface molecules including the PEDF Receptor, Laminin Receptor, LRP-6, and the F1 ATP Synthase (5, 9-13). It also has binding affinity for several extracellular matrix components, such as Heparin, Heparin Sulphate, Hyaluronan, and Collagens (5, 3). It is believed that the multiple and varied biological activities attributed to Serpin F1 are due to its interactions with these different cell surface molecules. Serpin F1 has been shown to be involved in neurogenesis, neuronal cell survival, angiogenesis, tumorgenesis, stem cell survival and multipotency, and inflammation (2-5, 10, 12-15). In humans, Serpin F1 has been suggested to play a role in choroidal neovascularization, obesity and insulin resistance, cardiovascular disease, osteogenesis imperfecta, and cancer (3-5, 15-19).