Strain induces Caco-2 intestinal epithelial proliferation and differentiation via PKC and tyrosine kinase signals.
Although the intestinal epithelium undergoes complex deformations during normal function, nutrient absorption, fasting, lactation, and disease, the effects of deformation on intestinal mucosal biology are poorly understood. We previously demonstrated that 24 h of cyclic deformation at an average 10% deformation every 6 s stimulates proliferation and modulates brush-border enzyme activity in human intestinal Caco-2 cell monolayers. In the present study we sought potential mechanisms for these effects. Protein kinase C (PKC) activity increased within 1 min after initiation of cyclic deformation, and the PKC-alpha and -zeta isoforms translocated from the soluble to the particulate fraction. Cyclic deformation also rapidly increased tyrosine kinase activity. Tyrosine phosphorylation of several proteins was increased in the soluble fraction but decreased in the particulate fraction by cyclic deformation for 30 min. Inhibition of PKC and tyrosine kinase signals by calphostin C, G-06967, and erbstatin attenuated or blocked cyclic deformation-mediated modulation of Caco-2 DNA synthesis and differentiation. These results suggest that cyclic deformation may modulate intestinal epithelial proliferation and brush-border enzyme activity by regulating PKC and tyrosine kinase signals.
Han
O
O
Department of Surgery, Yale University School of Medicine, New Haven 06520-8062, USA.
Li
G D
GD
Sumpio
B E
BE
Basson
M D
MD
D018938:Caco-2 Cells; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000166:cytology* / Q000201:enzymology / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008871:Microvilli / Q000201:enzymology; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013314:Stress, Mechanical; D014407:Tumor Cells, Cultured; D000099221:Protein Kinase C zeta
D004791:Enzyme Inhibitors; D006873:Hydroquinones; D007527:Isoenzymes; D009281:Naphthalenes; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D011505:Protein-Tyrosine Kinases; D000099221:Protein Kinase C zeta; C061465:calphostin complex; C496628:PRKCA protein, human; C048212:erbstatin