HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M800366-JLR200v1 50/2/285    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vaughan, A. M. Articles by Oram, J. F. Search for Related Content PubMed PubMed Citation Articles by Vaughan, A. M. Articles by Oram, J. F. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 50, 285-292, February 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation^*

Ashley M. Vaughan, Chongren Tang and John F. Oram¹

Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, Box 356426, University of Washington, Seattle, WA 98195

^* This work was supported by National Institutes of Health Grant RO1HL-55362.

Published, JLR Papers in Press, September 5, 2008.

¹ To whom correspondence should be addressed. e-mail: joram{at}u.washington.edu

ABCA1 exports cholesterol and phospholipids from cells by a multistep pathway that involves forming cell surface lipid domains, solubilizing these lipids by apolipoproteins, binding of apolipoproteins to ABCA1, and activating signaling processes. Here we used a mutational analysis approach to evaluate the relationship between these events. We prepared seven naturally occurring mutants and one artificial missense mutant of ABCA1 with varying degrees of impaired function, expressed them to similar levels as wild-type ABCA1 on the cell surface of BHK cells, and measured ABCA1-dependent lipid export, apolipoprotein A-I (apoA-I) binding, and signaling activities. Linear regression analyses showed that cholesterol and phospholipid efflux and cellular apoA-I binding correlated significantly with the ability of ABCA1 to form cell surface lipid domains. Lipid export and cellular apoA-I binding activities and formation of lipid domains also correlated with the amount of apoA-I that could be cross-linked to ABCA1. Moreover, each of these lipid export and apoA-I binding activities correlated with apoA-I-induced Janus kinase 2 (JAK2) activation. Thus, these missense mutations in ABCA1 impair lipid export, apoA-I binding, and apoA-I-stimulated JAK2 activities to similar extents, indicating that these processes are highly interactive components of a pathway that functions to export lipids from cells.

Supplementary key words ABCA1 mutations • apolipoprotein A-I • cholesterol efflux • phospholipid efflux • JAK2 activation

Abbreviations: apoA-I, apolipoprotein A-I; BHK, baby hamster kidney; JAK2, Janus kinase 2; NBD, nucleotide binding domain

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Tang, Y. Liu, P. S. Kessler, A. M. Vaughan, and J. F. Oram The Macrophage Cholesterol Exporter ABCA1 Functions as an Anti-inflammatory Receptor J. Biol. Chem., November 20, 2009; 284(47): 32336 - 32343. [Abstract] [Full Text] [PDF]

				D. Sviridov Maturation of apolipoprotein A-I: unrecognized health benefit or a forgotten rudiment? J. Lipid Res., July 1, 2009; 50(7): 1257 - 1258. [Full Text] [PDF]