Small proline-rich proteins (SPRR) function as SH3 domain ligands, increase resistance to injury and are associated with epithelial-mesenchymal transition (EMT) in cholangiocytes.
OBJECTIVE
Deficient biliary epithelial cell (BEC) expression of small proline-rich protein (SPRR) 2A in IL-6(-/-) mice is associated with defective biliary barrier function after bile duct ligation. And numerous gene array expression studies show SPRR2A to commonly be among the most highly up-regulated genes in many non-squamous, stressed and remodeling barrier epithelia. Since the function of SPRR in these circumstances is unknown, we tested the exploratory hypothesis that BEC SPRR2A expression contributes to BEC barrier function and wound repair.


METHODS
The effect of SPRR2A expression was studied in primary mouse BEC cultures; in a BEC cell line after forced overexpression of SPRR2A; and in human livers removed at the time of liver transplantation.


RESULTS
Forced SPRR2A overexpression showed that it functions as a SH3 domain ligand that increases resistance to oxidative injury and promotes wound restitution by enhancing migration and acquisition of mesenchymal characteristics. Low confluency non-neoplastic mouse BEC cultures show a phenotype similar to the stable transfectants, as did spindle-shaped BEC participating in atypical ductular reactions in primary biliary cirrhosis.


CONCLUSIONS
These observations suggest that SPRR2A-related BEC barrier modifications represent a novel, but widely utilized and evolutionarily conserved, response to stress that is worthy of further study.
D000818:Animals; D001652:Bile Ducts / Q000473:pathology*; D015820:Cadherins / Q000032:analysis; D002465:Cell Movement; D002478:Cells, Cultured; D055233:Cornified Envelope Proline-Rich Proteins; D004847:Epithelial Cells / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D053539:Keratin-19 / Q000032:analysis; D008024:Ligands; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000473:pathology*; D051379:Mice; D018384:Oxidative Stress; D014945:Wound Healing; D018909:src Homology Domains
D015820:Cadherins; D055233:Cornified Envelope Proline-Rich Proteins; D015850:Interleukin-6; D053539:Keratin-19; D008024:Ligands; D008565:Membrane Proteins; C101744:SPRR2A protein, human; C491091:Sprr2a1 protein, mouse