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Molecular and Cellular Biology, January 2001, p. 438-448, Vol. 21, No. 2
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.2.438-448.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Lipopolysaccharide-Induced Activation of beta 2-Integrin Function in Macrophages Requires Irak Kinase Activity, p38 Mitogen- Activated Protein Kinase, and the Rap1 GTPase

Anja Schmidt,1 Emmanuelle Caron,1 and Alan Hall1,2,3,*

MRC Laboratory for Molecular Cell Biology,1 CRC Oncogene and Signal Transduction Group,2 and Department of Biochemistry and Molecular Biology,3 University College London, London WC1E 6BT, United Kingdom

Received 21 August 2000/Returned for modification 5 October 2000/Accepted 30 October 2000

Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, is a potent activator of macrophages. Besides inducing many transcriptional pathways, LPS also elicits rapid morphological changes such as cell spreading. Here we have investigated the signaling pathway that controls macrophage beta 2-integrin-dependent spreading in response to LPS. We show that inhibition of the adapter protein MyD88, the interleukin-1 receptor-associated kinase Irak, the p38 mitogen-activated protein kinase, or the Ras-like GTPase Rap1 blocks LPS-induced spreading. In addition, Irak activates p38 and stimulates p38-dependent spreading. The activation of p38 by Irak requires Irak's kinase activity. We find that p38 controls spreading independently of its role in transcription but rather through activation of Rap1. Together, our results suggest that beta 2-integrin-dependent spreading of macrophages in response to LPS is controlled by a linear signaling pathway via MyD88, Irak, p38, and Rap1.

* Corresponding author. Mailing address: MRC Laboratory for Molecular Cell Biology, University College London, Gower St., London WC1E 6BT, United Kingdom. Phone: 44 (0)20 7679 7909. Fax: 44 (0)20 7679 7805. E-mail: alan.hall{at}ucl.ac.uk.

Molecular and Cellular Biology, January 2001, p. 438-448, Vol. 21, No. 2
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.2.438-448.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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