Evidence that tyrosine phosphorylation regulates N-cadherin turnover during retinal development.
N-cadherin, a member of the cadherin family of calcium-dependent cell adhesion molecules, mediates adhesive and signaling interactions between cells during development. N-Cadherin undergoes dynamic spatiotemporal changes in expression which correlate with morphogenetic movements of cells during organogenesis and histogenesis. We have previously shown that N-cadherin expression during development is regulated by several mechanisms, including mRNA expression, cytokine modulation, and proteolytically mediated turnover, yielding the NCAD90 protein. The present study was directed at determining the extent to which N-cadherin in primary embryonic cells is the target of endogenous kinases and phosphatases, as well as the effects of modulation of these enzymes on NCAD90 expression. The results of phosphoamino acid analyses, peptide mapping, and measurements of N-cadherin and NCAD90 expression in embryonic tissues indicate that N-cadherin is indeed the target of endogenous kinase and phosphatase action, and that modulation of different classes of these enzymes can result in either stimulation or inhibition of NCAD90 production. These results provide a mechanistic explanation for observations that cadherin function is downregulated following expression of exogenously introduced viral tyrosine kinases and provide a function for the tyrosine phosphatases recently found in association with cadherins. The results indicate that N-cadherin expression during retinal development is possibly regulated in part by modulation of its phosphorylation state, the balance of which may determine whether N-cadherin remains stably expressed or is targeted for proteolytically mediated turnover to produce NCAD90.
Lee
M M
MM
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Fink
B D
BD
Grunwald
G B
GB
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000196:embryology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007908:Lens, Crystalline / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009924:Organ Culture Techniques; D010449:Peptide Mapping; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012160:Retina / Q000196:embryology* / Q000378:metabolism; D013449:Sulfonamides; D014443:Tyrosine / Q000378:metabolism*; D014638:Vanadates / Q000494:pharmacology
D015820:Cadherins; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D013449:Sulfonamides; D010768:Phosphoserine; D014638:Vanadates; D014443:Tyrosine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D017027:Protein Tyrosine Phosphatases