Gordon W. Laurie, PhD
Characterization of extracellular regulators of epithelial differentiation in normal and cancer cells
The Laurie lab is focused on extracellular regulators of epithelial differentiation. Human 'lacritin' is the center of much of the lab's current and future research interests. Lacritin is a novel prosecretory mitogen discovered by them (Sanghi et al, J. Mol. Biol. 310: 127 - 139, 2001), and recently found to be related to the neural survival factor/breast cancer oncogene DCD. Both are co-amplified in some invasive human breast cancers. One group has described lacritin as the second most frequent SAGE marker for breast cancer among 8400 markers. Lacritin promotes mitogenesis via a pertussis toxin inhibitable signaling pathway involving PLC, IP3, PKC, PLD, NFAT and mTOR (Wang et al, in prep). Although its signaling receptor has not yet been identified, syndecan-1 serves as a co-receptor (Ma et al, in prep). Lacritin binding is to the syndecan-1 core protein, unlike FGF's and Wnts that bind to syndecan-1's heparan sulfate side chains. The latter actually inhibit lacritin binding, thus providing an elegant manner by which lacritin-dependent proliferation may be regulated - likely by local heparanase digestion. With lacritin deletion constructs, the lab has narrowed the mitogenic domain to a C-terminal region. Current and future studies are studying the mitogenic pathway in more detail, the nature of the expected GPCR signaling receptor, the binding site on syndecan-1, the effect of overexpressing lacritin in mouse mammary and other glands, and structural requirements for function.