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A novel interaction between protein kinase D and TNF receptor-associated factor molecules regulates B cell receptor-CD40 synergy
Journal article   Peer reviewed

A novel interaction between protein kinase D and TNF receptor-associated factor molecules regulates B cell receptor-CD40 synergy

Sokol A Haxhinasto and Gail A Bishop
The Journal of immunology (1950), Vol.171(9), pp.4655-4662
11/01/2003
DOI: 10.4049/jimmunol.171.9.4655
PMID: 14568940

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Abstract

Signaling by Ag to the B cell Ag receptor (BCR) is enhanced by several cooperating signals, including several provided by B-T cell interactions. One of these, CD40, provides critical signals for B cell differentiation, isotype switching, and B cell memory. The molecular mechanisms by which BCR and CD40 signals synergize are not well understood. Although the BCR and CD40 share certain signaling pathways, we hypothesized that unique signals provided by each could provide mutual enhancement of their signaling pathways. The BCR, but not CD40, activates protein kinase D (PKD), while CD40, but not the BCR, employs the TNFR-associated factor (TRAF) adapter proteins in signaling. In this study, we show that genetic or pharmacologic inhibition of BCR-mediated PKD activation in B lymphocytes abrogated the synergy between the CD40 and the BCR, as measured by activation of Ig and cytokine secretion. Interestingly, the role of PKD was dependent upon the association of CD40 with TRAF2, and was inhibited by the binding of TRAF3, revealing a novel functional link between these two classes of signaling molecules.
 Protein Binding - genetics Humans Receptors, Antigen, B-Cell - metabolism TNF Receptor-Associated Factor 1 Enzyme Activation - immunology Receptors, Tumor Necrosis Factor - physiology TNF Receptor-Associated Factor 2 TNF Receptor-Associated Factor 3 Signal Transduction - immunology CD40 Antigens - metabolism Isoenzymes - metabolism Protein Kinase C - metabolism Receptors, Antigen, B-Cell - physiology Isoenzymes - physiology Receptors, Tumor Necrosis Factor - metabolism CD40 Antigens - physiology Cell Line Proteins - physiology Protein Kinase C - physiology Mice, Inbred C57BL Cells, Cultured Enzyme Inhibitors - pharmacology Up-Regulation - genetics Protein Kinase C - antagonists & inhibitors Receptors, Antigen, B-Cell - antagonists & inhibitors Signal Transduction - genetics Enzyme Activation - drug effects Protein Binding - immunology Drug Synergism Proteins - genetics Animals Proteins - metabolism Signal Transduction - drug effects Up-Regulation - immunology 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology Mice Enzyme Activation - genetics Isoenzymes - antagonists & inhibitors Staurosporine - pharmacology

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