Selective role of PKCbeta enzymatic function in regulating cell survival mediated by B cell antigen receptor cross-linking.

Abstract

Cross-linking of the B cell antigen receptor (BCR) results in the activation of several protein tyrosine kinases leading to phospholipase C-gamma2-dependent phospholipid hydrolysis and Ca2+ mobilization, followed by activation of the protein kinase C (PKC) family members. Sustained Ca2+ release in B lymphocytes is dependent on the membrane localization and activation of the protein tyrosine kinase BTK. Ca2+ release is a tightly regulated process involving BTK membrane localization through its phosphorylation by PKCbeta. A selective role of PKCbeta in B cell signaling was first revealed by the characterization of PKCbeta knockout mice, which displayed decreased B cell proliferation in response to various mitogenic stimuli. However, it is not clear whether the B cell defects displayed by the PKCbeta knockout mice are due a B cell developmental defect or the scaffolding function of PKCbeta, resulting in a defect in the recruitment or formation of signal transducing complex molecules. Thus, in this report we investigated the effects of pharmacologic inhibition of the catalytic function of PKCbeta on B cell survival and growth. Treatment of Daudi B lymphoma cell line with a selective PKCbeta inhibitor, LY333531, inhibited anti-IgM-induced phosphorylation of BTK on Ser180 in a concentration-dependent manner, which was concomitant with an increase in BTK activation, and Ca2+ mobilization. In primary splenic B cells, LY333531 inhibited BCR-induced B cell proliferation, but did not affect basal or LPS-induced proliferation. Finally, LY333531 treatment resulted in the induction of apoptosis of anti-IgM-activated B cells, which corroborated with their inability to up-regulate pro-survival factors, Bcl-X(L) and Bcl-2. These results support the important and selective role of the PKCbeta enzymatic function in controlling Ca2+ release during BCR signaling leading to B lymphocyte survival and growth.

• Authors: Chandrasekar Venkataraman, Xinyi Cynthia Chen, Songqing Na, Linda Lee, Kuldeep Neote, Seng-Lai Tan
• Journal: Immunology letters (Immunol Lett) Vol. 105 Issue 1 Pg. 83-9 (May 15 2006) ISSN: 0165-2478 [Print] Netherlands
• PMID: 16564096 (Publication Type: Journal Article)

Chemical References

• Cross-Linking Reagents
• Indoles
• Maleimides
• Protein Kinase Inhibitors
• Receptors, Antigen, B-Cell
• ruboxistaurin
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• Protein Kinase C
• Protein Kinase C beta

Topics

• Agammaglobulinaemia Tyrosine Kinase
• Animals
• B-Lymphocytes (cytology, drug effects, enzymology, immunology)
• Calcium Signaling (drug effects)
• Cell Survival
• Cross-Linking Reagents
• Female
• In Vitro Techniques
• Indoles (pharmacology)
• Maleimides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Protein Kinase C (antagonists & inhibitors, immunology, metabolism)
• Protein Kinase C beta
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (metabolism)
• Receptors, Antigen, B-Cell (metabolism)