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 alpha-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 Galpha(i) or Galpha(o)-PKCalpha-PLC-Ca2+-calcineurin-NFATC1 
and Galpha(i) or Galpha(o)-PKCalpha-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 PKCalpha upstream of both Ca2+ mobilization and 
PLD activation in a complex with PLCgamma2. 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.