Gordon W. Laurie

Education

  • PhD, McGill University

Primary Appointment

  • Associate Professor, Cell Biology

Contact

Research Interest(s)

Epithelial Renewal, Viability and Secretion

Research Description

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 tearing (Sanghi et al, '01). Tears are responsible for homeostasis of the surface of the eye and are essential for innate defense (Karnati et al, '13). Both functions are in whole or part contributed by lacritin (Wang et al, ’13) or by cleavage potentiated fragments of lacritin (McKown et al, submitted). 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, '06; Zhang et al, ‘13). Binding is mutually specified by lacritin's C-terminal mitogenic/prosurvival/prosecretory domain (Wang et al, ’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, ’06; ’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 FOX1 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, ’13). New areas will explore: (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 Lacritin Consortium of collaborating labs meets several times a year.

Selected Publications

  • Karnati R, Laurie D, Laurie G. Lacritin and the tear proteome as natural replacement therapy for dry eye. Experimental eye research. 2013;117 39-52. PMID: 23769845
  • McKown R, Raab R, Kachelries P, Caldwell S, Laurie G. Conserved regional 3' grouping of rare codons in the coding sequence of ocular prosecretory mitogen lacritin. Investigative ophthalmology & visual science. 2013;54(3): 1979-87. PMID: 23422824
  • Velez V F, Romano J, McKown R, Green K, Zhang L, Raab R, Ryan D, Hutnik C, Frierson H, Laurie G. Tissue transglutaminase is a negative regulator of monomeric lacritin bioactivity. Investigative ophthalmology & visual science. 2013;54(3): 2123-32. PMID: 23425695
  • Wang N, Zimmerman K, Raab R, McKown R, Hutnik C, Talla V, Tyler M, Lee J, Laurie G. Lacritin rescues stressed epithelia via rapid forkhead box O3 (FOXO3)-associated autophagy that restores metabolism. The Journal of biological chemistry. 2013;288(25): 18146-61. PMID: 23640897
  • Zhang Y, Wang N, Raab R, McKown R, Irwin J, Kwon I, van Kuppevelt T, Laurie G. Targeting of heparanase-modified syndecan-1 by prosecretory mitogen lacritin requires conserved core GAGAL plus heparan and chondroitin sulfate as a novel hybrid binding site that enhances selectivity. The Journal of biological chemistry. 2013;288(17): 12090-101. PMID: 23504321