Signal transduction via leukocyte antigen CD43 (sialophorin). Feedback regulation by protein kinase C.
CD43 is a constitutively phosphorylated 115-kDa sialoglycoprotein expressed on a variety of blood cells including lymphocytes and monocytes. L10, a mAb directed against CD43, triggers T cell activation and enhances hydrogen peroxide production in monocytes. Activation of mononuclear cells by L10 initiates phosphoinositides hydrolysis, C2+ mobilization, and protein kinase C (PKC) activation. In turn, activated PKC hyperphosphorylates CD43, suggesting a potential role for PKC in the regulation of signaling via CD43. To address this issue, we have analyzed the effect of PKC activation by the tumor promoter PMA on L10-triggered rise in intracellular free Ca2+ concentrations ([Ca2+]i). Treatment of mononuclear cells with PMA profoundly inhibited the increase in [Ca2+]i induced by L10. The inhibition of CD43-mediated signaling by PMA was due, in part, to uncoupling of CD43 from the signal-transducing G protein. This was evidenced by the comparatively modest inhibition by PMA of the increase in [Ca2+]i induced by the direct G protein activator AlF4-. PMA treatment did not affect the surface expression of CD43. However, it induced the hyperphosphorylation of CD43, the extent of which correlated with the inhibition of CD43-mediated increase in [Ca2+]i. Staurosporine, a potent inhibitor of PKC, abrogated the hyperphosphorylation of CD43 and normalized CD43-mediated signaling in PMA-treated cells. Significantly, in the absence of PMA, staurosporine enhanced the rise in [Ca2+]i triggered by L10, suggesting that engagement of CD43 by activating ligands results in feedback inhibition by PKC. It is concluded that activation of PKC inhibits signaling via CD43 by mechanisms involving phosphorylation and uncoupling of CD43 from the signal-transducing apparatus and by distal, post-receptor events.
Wong
R C
RC
Division of Allergy and Immunology, Children's Hospital, Boston, MA 02115.
Remold-O'Donnell
E
E
Vercelli
D
D
Sancho
J
J
Terhorst
C
C
Rosen
F
F
Geha
R
R
Chatila
T
T
D000470:Alkaloids / Q000494:pharmacology; D000535:Aluminum / Q000494:pharmacology; D017607:Aluminum Compounds; D015703:Antigens, CD / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism; D005459:Fluorides / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D051917:Leukosialin; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D012795:Sialoglycoproteins / Q000502:physiology*; D015398:Signal Transduction; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D017607:Aluminum Compounds; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D051917:Leukosialin; D011948:Receptors, Antigen, T-Cell; C465014:SPN protein, human; D012795:Sialoglycoproteins; D000535:Aluminum; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D005459:Fluorides; D002118:Calcium; C032311:aluminum fluoride