Restricted epithelial proliferation by lacritin via PKCalpha-dependent NFAT and mTOR pathways.
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.
Wang
Jiahu
J
Department of Cell Biology, University of Virginia, Charlottesville, VA 22904, USA.
Wang
Ningning
N
Xie
Jinling
J
Walton
Staci C
SC
McKown
Robert L
RL
Raab
Ronald W
RW
Ma
Peisong
P
Beck
Shannon L
SL
Coffman
George L
GL
Hussaini
Isa M
IM
Laurie
Gordon W
GW
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology*; D006056:Golgi Apparatus / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D011487:Protein Conformation; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D021381:Protein Transport; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D006023:Glycoproteins; D006133:Growth Substances; C431764:LACRT protein, human; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051571:Protein Kinase C-alpha; D010739:Phospholipase D; D002118:Calcium