Restricted epithelial proliferation by lacritin via PKCα-dependent NFAT and mTOR pathways

Abstract

Renewal of nongermative epithelia is poorly understood. The novel mitogen “lacritin” is apically secreted by several nongermative epithelia. We tested 17 different cell types and discovered that lacritin is preferentially mitogenic or prosecretory for those types that normally contact lacritin during its glandular outward flow. Mitogenesis is dependent on lacritin's C-terminal domain, which can form an α-helix with a hydrophobic face, as per VEGF's and PTHLP's respective dimerization or receptor-binding domain. Lacritin targets downstream NFATC1 and mTOR. The use of inhibitors or siRNA suggests that lacritin mitogenic signaling involves Gαi or Gαo–PKCα-PLC–Ca2+–calcineurin–NFATC1 and Gαi or Gαo–PKCα-PLC–phospholipase D (PLD)–mTOR in a bell-shaped, dose-dependent manner requiring the Ca2+ sensor STIM1, but not TRPC1. This pathway suggests the placement of transiently dephosphorylated and perinuclear Golgi–translocated PKCα upstream of both Ca2+ mobilization and PLD activation in a complex with PLCγ2. Outward flow of lacritin from secretory cells through ducts may generate a proliferative/secretory field as a different unit of cellular renewal in nongermative epithelia where luminal structures predominate.

Deoxycorticosterone Acetate-Salt Mice Exhibit Blood Pressure–Independent Sexual Dimorphism

“…For instance, the novel mitogen "lacritin" was found recently to target the downstream nuclear factor of activated T cell and the mammalian target of rapamycin via a protein kinase C-␣-dependent mechanism. 35 These complex signaling pathways open numerous potential therapeutic targets for our findings.…”

mTOR signaling: PLD takes center stage

“…26 A PLD1-mTOR pathway is also found to be required for skeletal myoblast differentiation by regulating the expression of insulin-like growth factor II. 72 Furthermore, mTOR activation in Syk-dependent survival of follicular lymphoma cells, 82 lacritin regulation of restricted epithelial proliferation, 83 melanogenesis of mouse B16 melanoma cells, 84 and collagen type I production in human dermal fibroblasts 85 all involve PLD and PA.…”

Focus on Molecules: Lacritin

“…Lacritin appears to promote constitutive tear secretion in cultured lacrimal acinar cells, possibly via an autocrine stimulatory mechanism (Sanghi et al, 2001). Lacritin also stimulates human corneal epithelial (HCE-T) cell proliferation via a biphasic 1 -10 nM dose optimum, but has no apparent mitogenic effect on fibroblasts, glia or erythroleukemic cells, and epithelia from epidermis, breast cancer, melanoma or testes (Wang et al, 2006). Cell specificity is generated by a unique 'off-on' switch mechanism in which heparanase deglycanation of cell surface SDC1 exposes a lacritin binding site in the N-terminus of SDC1 as a prerequisite for lacritin mitogenic signaling .…”

“…Cell specificity is generated by a unique 'off-on' switch mechanism in which heparanase deglycanation of cell surface SDC1 exposes a lacritin binding site in the N-terminus of SDC1 as a prerequisite for lacritin mitogenic signaling . Lacritin mitogenic signaling targets Gα i or Gα o /PKCα-PLC/Ca 2+ /calcineurin/NFATC1 and Gα i or Gα o /PKCα-PLC/PLD/mTOR (Wang et al, 2006). Thus, lacritin is an eye-specific growth factor that may play an important role in secretion and renewal of lacrimal and ocular surface epithelia.…”