Enhancement of migration by protein kinase Calpha and inhibition of proliferation and cell cycle progression by protein kinase Cdelta in capillary endothelial cells.
Activation of protein kinase C (PKC) induces angiogenesis, migration, and proliferation of endothelial cells (EC), but can also prevent growth factor-induced EC proliferation. To determine whether these disparate effects are mediated by substrates of individual PKC isoenzymes, PKCalpha and PKCdelta were overexpressed in rat microvascular EC. Basal and stimulated migration were enhanced in PKCalpha EC compared with either PKCdelta or control EC. Serum-induced growth of PKCdelta EC was decreased, while that of PKCalpha cells was similar to control EC. Phorbol ester markedly inhibited PKCdelta EC growth but enhanced growth of PKCalpha and control EC. To determine possible causes for this altered proliferation, the effect of PKCdelta on adhesion, mitogen-activated protein kinase activity, and cell cycle progression was measured. Adherence of PKCdelta EC to vitronectin was significantly enhanced. Serum-induced extracellular signal-regulated kinase-2 activity was increased equally in both PKCalpha and PKCdelta EC above that of control, while extracellular signal-regulated kinase-1 activity was similar in all EC. Cell cycle analysis suggested that PKCdelta EC entered S phase inappropriately and were delayed in passage through S phase. Thus, PKCalpha may mediate some proangiogenic effects of PKC activation; conversely, PKCdelta may direct antiangiogenic aspects of overall PKC activation, including slowing of the cell cycle progression.
Harrington
E O
EO
Department of Medicine, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA.
Löffler
J
J
Nelson
P R
PR
Kent
K C
KC
Simons
M
M
Ware
J A
JA
D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D007527:Isoenzymes / Q000235:genetics*; D011493:Protein Kinase C / Q000235:genetics*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051381:Rats
D007527:Isoenzymes; C497260:Prkcd protein, rat; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta