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Published online 21 August 2006. doi:10.1083/jcb.200605140
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 5, 689-700
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Article

Restricted epithelial proliferation by lacritin via PKC{alpha}-dependent NFAT and mTOR pathways



Jiahu Wang1, Ningning Wang1, Jinling Xie1, Staci C. Walton1, Robert L. McKown3, Ronald W. Raab3, Peisong Ma1, Shannon L. Beck1, George L. Coffman3, Isa M. Hussaini2, and Gordon W. Laurie1

1 Department of Cell Biology and 2 Department of Pathology, University of Virginia, Charlottesville, VA 22904
3 Department of Integrated Science and Technology, James Madison University, Harrisonburg, VA 22807

Correspondence to Gordon W. Laurie: glaurie{at}virginia.edu

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 G{alpha}i or G{alpha}o–PKC{alpha}-PLC–Ca2+–calcineurin–NFATC1 and G{alpha}i or G{alpha}o–PKC{alpha}-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 PKC{alpha} upstream of both Ca2+ mobilization and PLD activation in a complex with PLC{gamma}2. 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.

J. Wang, N. Wang, and J. Xie contributed equally to this paper.

Abbreviations used in this paper: CsA, cyclosporin A; HCE, human corneal epithelial; HSG, human salivary ductal; PLD, phospholipase D; PM, plasma membrane; PNG, perinuclear Golgi region; PTX, pertussis toxin; SF, serum-free; SOC, store-operated Ca2+.


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