cDNA and genomic cloning of lacritin, a novel secretion enhancing factor from the human lacrimal gland

Multiple extracellular factors are hypothesized to promote the differentiat ion of unstimulated and/or stimulated secretory pathways in exocrine secret ory cells, but the identity of differentiation factors, particularly those organ-specific, remain largely unknown. Here, we report on the identificati on of a novel secreted glycoprotein, lacritin, that enhances exocrine secre tion in overnight cultures of lacrimal acinar cells which otherwise display loss of secretory function. Lacritin mRNA and protein are highly expressed in human lacrimal gland, moderately in major and minor salivary glands and slightly in thyroid. No lacritin message or protein is detected elsewhere among more than 50 human tissues examined. Lacritin displays partial simila rity to the glycosaminoglycan-binding region of brain-specific neuroglycan C (32% identity over 102 amino acid residues) and to the possibly mucin-lik e amino globular region of fibulin-2 (30% identity over 81 amino acid resid ues), and localizes primarily to secretory granules and secretory fluid. Th e lacritin gene consists of five exons, displays no alternative splicing an d maps to 12q13. Recombinant lacritin augments unstimulated but not stimula ted acinar cell secretion, promotes ductal cell proliferation, and stimulat es signaling through tyrosine phosphorylation and release of calcium. It bi nds collagen TV, laminin-1, entactin/nidogen-1, fibronectin and vitronectin , but not collagen I, heparin or EGF. As an autocrine/paracrine enhancer of the lacrimal constitutive secretory pathway, ductal cell mitogen and stimu lator of corneal epithelial cells, lacritin may play a key role in the func tion of the lacrimal gland-corneal axis. (C) 2001 Academic Press.