Lipopolysaccharide-induced activation of beta2-integrin function in macrophages requires Irak kinase activity, p38 mitogen- activated protein kinase, and the Rap1 GTPase.
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 beta2-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 beta2-integrin-dependent spreading of macrophages in response to LPS is controlled by a linear signaling pathway via MyD88, Irak, p38, and Rap1.
Schmidt
A
A
MRC Laboratory for Molecular Cell Biology, University College London, London WC1E 6BT, United Kingdom.
Caron
E
E
Hall
A
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048669:MAP Kinase Kinase 6; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008845:Microinjections; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D053594:Myeloid Differentiation Factor 88; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D000943:Antigens, Differentiation; D018821:CD18 Antigens; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011971:Receptors, Immunologic; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482567:Map2k6 protein, mouse; D020827:rap1 GTP-Binding Proteins