Laurie, Gordon W.
Professor, Cell Biology
- BS, Biology, McMaster University
- MS, Cell Biology, McGill University, Montreal, P.Q., CANADA
- PhD, Cell Biology, McGill University, Montreal, P.Q., CANADA
Role of Prosecretory Mitogen 'Lacritin' in Epithelial Homeostasis, Secretion and Innate Defense
My lab is interested in epithelial homeostasis, secretion and innate defense. We focus on the human prosecretory mitogen 'lacritin' that we discovered and named out of an unbiased screen for factors regulating ocular tearing (Sanghi et al, J Mol Biol '01). Tears are responsible for homeostasis of the surface of the eye and are essential for innate defense (Karnati et al, Exp Eye Res '13). Both functions are in whole or part contributed by lacritin (Wang et al, J Biol Chem '13) or by cleavage potentiated fragments of lacritin (McKown et al, J Biol Chem, '14). Our exploration of lacritin cell targeting led to the discovery of a novel 'off/on' switch mechanism in which lacritin binding of the ubiquitous cell surface proteoglycan 'syndecan-1' requires prior removal of heparan sulfate chains by 'heparanase' (Ma et al, J Cell Biol '06; Zhang et al, J Biol Chem '13). Binding is mutually specified by lacritin's C-terminal mitogenic/prosurvival/prosecretory domain (Wang et al, J Cell Biol '06) and syndecan-1's N-terminus via a highly selective mechanism requiring the hydrophobic GAGAL sequence, cleaved heparan sulfate and an N-terminal chondroitin sulfate chain in syndecan-1. Truncation and point mutational analysis has narrowed the active site in lacritin to an amphipathic alpha helix (Wang et al, J Cell Biol '06; J Biol Chem '13). Lacritin mitogenic and prosurvival signaling is rapid (within 20 sec) and likely initiated by a G-protein coupled receptor. Prosurvival signaling involves acetylation of FOXO3 to couple with autophagy mediator ATG101, as well as phosphorylation of FOXO1 to couple with ATG7. Thus in stressed epithelia, lacritin rapidly stimulates autophagy. This is transient and sufficient to remove stress-damaged proteins. Lacritin independently stimulates oxidative phosphorylation and mitochondrial fusion (Wang et al, J Biol Chem '13). New areas of research are exploring: (i) the lacritin signaling receptor, (ii) lacritin mitochondrial signaling, (iii) direct or indirect targeting of sensory neurons, and (iv) lacritin's cleavage-potentiated bactericidal activity. A UVa-based startup company was recently spun-off to take lacritin through phase II human clinical trials for 'dry eye', the most common eye disease. Twelve years ago, I organized the multi-institutional (UVa, James Madison, Eastern Virginia Medical School, Cornell, Johns Hopkins, UCSF, US Army at Fort Belvoir) Lacritin Consortium of collaborating labs. The Consortium has continuously met two to three times a year since 2002 to share data and explore new projects.