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Originally published In Press as doi:10.1074/jbc.M708069200 on November 8, 2007

J. Biol. Chem., Vol. 283, Issue 2, 929-939, January 11, 2008
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3-Phosphoinositide-dependent Kinase 1 Deficiency Perturbs Toll-like Receptor Signaling Events and Actin Cytoskeleton Dynamics in Dendritic Cells*Formula

Rossana Zaru, Pamela Mollahan, and Colin Watts1

From the Division of Cell Biology and Immunology, Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom

The adaptive immune response depends on dendritic cell (DC) activation by microbial products that signal via pattern recognition receptors and activate mitogen-activated protein kinases, NF{kappa}B and PI3K. The contribution of the AGC kinase family, including protein kinase B, protein kinase C, p90kDa ribosomal S6 kinase, and S6 kinase, has been little investigated because the probable redundancy among their isoforms makes their study difficult. We took advantage of the fact that all these kinases are regulated by the upstream master kinase 3-phosphoinositide-dependent kinase 1 (PDK1). Here we analyze various properties of DC from mice expressing ~10% of normal PDK1 (PDK1fl/–). DC populations in lymphoid and nonlymphoid tissues appeared normal in PDK1fl/– mice, and some in vitro responses to lipopolysaccharide (LPS) such as cytokine production were normal in cultured bone marrow DC. However, LPS-induced expression of class II major histocompatibility complex and CD86 were elevated in PDK1fl/– BMDC and PDK1fl/– spleen DC produced more interleukin-10 and -12, implying an attenuating role for PDK1. Unexpectedly, PDK1fl/– DC had a significantly reduced capacity for LPS-stimulated macropinocytosis and phagocytosis that correlated with a lowered F-actin/G-actin ratio, apparently because of increased actin depolymerization. Several PDK1-regulated kinases, some of which feed into actin regulators, showed reduced activation in PDK1fl/– DC. Reintroduction of PDK1 restored S6 kinase activity, increased levels of F-actin, and boosted macropinocytosis thus linking PDK1 and its downstream effectors to the unusual phenotype of PDK1fl/– DC.


Received for publication, September 27, 2007 , and in revised form, November 1, 2007.

* This work was supported by a Medical Research Council Programme grant (to C. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Formula The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

1 To whom correspondence should be addressed: Division of Cell Biology and Immunology, Wellcome Trust Biocentre, University of Dundee, Dow St., Dundee DD1 5EH, UK. Tel.: 44-1382-384233; Fax: 44-1382-385783; E-mail: c.watts{at}dundee.ac.uk.


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