View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector

FEBS Letters 581 (2007) 757–763

CD14 is a ligand for the integrin a4b1

Jonathan D. Humphries, Martin J. Humphries* Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom

Received 15 November 2006; revised 15 January 2007; accepted 18 January 2007

Available online 25 January 2007

Edited by Beat Imhof

to regulate the strengthening of cell–matrix interactions and to Abstract Cell adhesion mediated by the integrin a4b1 plays a key role in many biological processes reflecting both the number initiate new cell adhesion contacts [4]. and functional significance of a4b1 ligands. The lipopolysaccha- Integrins bind to all of their characterised ligands via a crit- ride (LPS) , CD14, is a GPI-linked cell surface glyco- ical acidic motif in a divalent cation-dependent manner [5]. with a wide range of reported functions and The a4b1 integrin (also known as VLA-4 or CD49d/CD29) associations, some of which overlap with that of a4b1. This over- is expressed on the surface of a variety of cell types, including lap led us to test the specific hypothesis that a4b1 and CD14 , , eosinophils and [6], and + interact directly. Jurkat T cells (a4b1 ) were found to adhere has so far been reported to bind to a wide variety of cell sur- to a recombinant CD14-Fc protein via a4b1, whilst K562 cells À face and extracellular matrix ligands [7] making it one of the (a4b1 ) did not. However, stable reexpression of the a4-subunit more promiscuous integrins. These binding partners include conferred this ability. The adhesion of both cell types to CD14 the classical a4b1 ligands, vascular cell adhesion molecule displayed activation state-dependent binding very similar to the interaction of a4b1 with its prototypic ligand, VCAM-1. In so- (VCAM-1) [8] and the alternatively spliced type III connecting lid-phase assays, CD14-Fc bound to affinity-purified a4b1ina segment of fibronectin (FN) [9,10], together with mucosal dose-dependent manner that was induced by activating anti-b1 addressin cell adhesion molecule-1 (MAdCAM-1) [11], osteo- mAbs. Finally, in related experiments, JY cells (a4b7+) were pontin [12], and thrombospondin [13]. Through these interac- also found to attach to CD14-Fc in an a4-dependent manner. tions, a4b1 plays an important role in embryonic development, In summary, CD14 is a novel ligand for a4b1, exhibiting similar adult homeostasis, and immune responses [6,14]. activation-state dependent binding characteristics as other a4b1 CD14 is a 55 kDa GPI-anchored, leucine-rich repeat (LRR) ligands. The biological relevance of this interaction will be the protein [15–17]. CD14 is expressed strongly on the surface of subject of further studies. monocytes and other myeloid cells, and is expressed at lower 2007 Federation of European Biochemical Societies. Pub- levels on B-lymphocytes, basophils, mammary cells, placental lished by Elsevier B.V. All rights reserved. trophoblasts, gingival fibroblasts [18] and low passage number Keywords: Integrin; CD14; Cell adhesion endothelial cells [19,20]. A soluble form of CD14 is also present in serum at lg/ml levels. CD14 is the major receptor for bacte- rial endotoxin (, LPS) and mediates innate immune responses [21,22]. The interaction of LPS with CD14 results in the release of inflammatory and the upreg- 1. Introduction ulation of adhesion molecules (b1 integrin and aLb2) [21].As CD14 does not possess a transmembrane domain, it is