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Journal of Lipid Research, Vol. 47, 794-803, April 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter

Jerzy-Roch Nofer^*,,1, Alan T. Remaley, Renata Feuerborn, Iza Wolinska^*, Thomas Engel, Arnold von Eckardstein^** and Gerd Assmann^*,

^* Institut für Klinische Chemie und Laboratoriumsmedizin, Westfälische Wilhelms-Universität, Münster, Germany
Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany
Department of Laboratory Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD
^** Institut für Klinische Chemie, Universitäts-Spital Zürich, Zürich, Switzerland

Published, JLR Papers in Press, January 28, 2006.

¹ To whom correspondence should be addressed. e-mail: nofer{at}uni-muenster.de

It has been suggested that the signal transduction initiated by apolipoprotein A-I (apoA-I) activates key proteins involved in cholesterol efflux. ABCA1 serves as a binding partner for apoA-I, but its participation in apoA-I-induced signaling remains uncertain. We show that the exposure of human fibroblasts to ABCA1 ligands (apolipoproteins and amphipathic helical peptides) results in the generation of intracellular signals, including activation of the small G-protein Cdc42, protein kinases (PAK-1 and p54^JNK), and actin polymerization. ApoA-I-induced signaling was abrogated by glyburide, an inhibitor of the ABC transporter family, and in fibroblasts from patients with Tangier disease, which do not express ABCA1. Conversely, induction of ABCA1 expression with the liver X receptor agonist, T0901317, and the retinoid X receptor agonist, R0264456, potentiated apoA-I-induced signaling. Similar effects were observed in HEK293 cells overexpressing ABCA1-green fluorescent protein (GFP) fusion protein, but not ABCA1-GFP (K939M), which fails to hydrolyze ATP, or a nonfunctional ABCA1-GFP with a truncated C terminus. We further found that Cdc42 coimmunoprecipitates with ABCA1 in ABCA1-GFP-expressing HEK293 cells exposed to apoA-I but not in cells expressing ABCA1 mutants. We conclude that ABCA1 transduces signals from apoA-I by complexing and activating Cdc42 and downstream kinases and, therefore, acts as a full apoA-I receptor.

Supplementary key words ATP binding cassette transporter A1 • high density lipoproteins • cholesterol efflux

Abbreviations: apoA-I, apolipoprotein A-I; GEF, GDP exchange factor; GFP, green fluorescent protein; GST-PBD, glutathione S-transferase-p21 binding domain; JAK2, Janus kinase 2; LXR, liver X receptor; PC, phosphatidylcholine; PKA, protein kinase A; PKC, protein kinase C; RXR, retinoid X receptor; WS, Werner syndrome

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