Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter

• Published in: Journal of lipid research 2006-04, Vol.47 (4), p.794-803
• Main Authors: Nofer, Jerzy-Roch, Remaley, Alan T., Feuerborn, Renata, Wolinnéska, Iza, Engel, Thomas, von Eckardstein, Arnold, Assmann, Gerd
• Format: Article
• Language: English
• Subjects: Aged; Apolipoprotein A-I - metabolism; ATP Binding Cassette Transporter 1; ATP binding cassette transporter A1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; cdc42 GTP-Binding Protein - metabolism; Cells, Cultured; Cholesterol - chemistry; Cholesterol - metabolism; cholesterol efflux; Enzyme Activation; Fibroblasts - cytology; Fibroblasts - metabolism; Glyburide - metabolism; high density lipoproteins; Humans; Hypoglycemic Agents - metabolism; Male; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Signal Transduction - physiology; Tangier Disease
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M500502-JLR200

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 p54JNK), 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.