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Molecular and Cellular Biology, February 2006, p. 1569-1577, Vol. 26, No. 4
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.4.1569-1577.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Essential Role for Protein Kinase D Family Kinases in the Regulation of Class II Histone Deacetylases in B Lymphocytes

Division of Cell Biology and Immunology, University of Dundee, Dundee, Scotland, United Kingdom,¹ Department of Pediatrics and Immunology and Children's Hospital and Regional Medical Center, University of Washington, Seattle, Washington,² Department of Molecular BiologyUT Southwestern Medical Center at Dallas, Dallas, Texas,³ Myogen, Inc., Westminster, Colorado⁴

Received 10 September 2005/ Returned for modification 3 October 2005/ Accepted 15 November 2005

We have taken a knockout approach to interrogate the function of protein kinase D (PKD) serine/threonine kinases in lymphocytes. DT40 B cells express two PKD family members, PKD1 and PKD3, which are both rapidly activated by the B-cell antigen receptor (BCR). DT40 cells with single or dual deletions of PKD1 and/or PKD3 were viable, allowing the role of individual PKD isoforms in BCR signal transduction to be assessed. One proposed downstream target for PKD1 in lymphocytes is the class II histone deacetylases (HDACs). Regulation of chromatin accessibility via class II histone deacetylases is an important mechanism controlling gene expression patterns, but the molecules that control this key process in B cells are not known. Herein, we show that phosphorylation and nuclear export of the class II histone deacetylases HDAC5 and HDAC7 are rapidly induced following ligation of the BCR or after treatment with phorbol esters (a diacylglycerol mimetic). Loss of either PKD1 or PKD3 had no impact on HDAC phosphorylation, but loss of both PKD1 and PKD3 abrogated antigen receptor-induced class II HDAC5/7 phosphorylation and nuclear export. These studies reveal an essential and redundant role for PKD enzymes in controlling class II HDACs in B lymphocytes and suggest that PKD serine kinases are a critical link between the BCR and epigenetic control of chromatin.

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