Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins.
Inside-out signaling regulation of the beta2-integrin leukocyte function-associated antigen-1 (LFA-1) by different cytoplasmic proteins, including 14-3-3 proteins, is essential for adhesion and migration of immune cells. Here, we identify a new pathway for the regulation of LFA-1 activity by Cbl-b, an adapter molecule and ubiquitin ligase that modulates several signaling ... pathways. Cbl-b-/- mice displayed increased macrophage recruitment in thioglycollate-induced peritonitis, which was attributed to Cbl-b deficiency in macrophages, as assessed by bone marrow chimera experiments. In vitro, Cbl-b-/- bone marrow-derived mononuclear phagocytes (BMDMs) displayed increased adhesion to endothelial cells. Activation of LFA-1 in Cbl-b-deficient cells was responsible for their increased endothelial adhesion in vitro and peritoneal recruitment in vivo, as the phenotype of Cbl-b deficiency was reversed in Cbl-b-/-LFA-1-/- mice. Consistently, LFA-1-mediated adhesion of BMDM to ICAM-1 but not VLA-4-mediated adhesion to VCAM-1 was enhanced by Cbl-b deficiency. Cbl-b deficiency resulted in increased phosphorylation of T758 in the beta2-chain of LFA-1 and thereby in enhanced association of 14-3-3beta protein with the beta2-chain, leading to activation of LFA-1. Consistently, disruption of the 14-3-3/beta2-integrin interaction abrogated the enhanced ICAM-1 adhesion of Cbl-b-/- BMDMs. In conclusion, Cbl-b deficiency activates LFA-1 and LFA-1-mediated inflammatory cell recruitment by stimulating the interaction between the LFA-1 beta-chain and 14-3-3 proteins.
Mesh Terms:
14-3-3 Proteins, Animals, Antigens, CD18, Cell Adhesion, Cell Line, Tumor, Cell Movement, Endothelium, Vascular, Humans, Inflammation, Integrin alpha4beta1, Intercellular Adhesion Molecule-1, Lymphocyte Function-Associated Antigen-1, Macrophages, Peritoneal, Mice, Mice, Knockout, Oncogene Protein v-cbl, Signal Transduction, Ubiquitin-Protein Ligases
14-3-3 Proteins, Animals, Antigens, CD18, Cell Adhesion, Cell Line, Tumor, Cell Movement, Endothelium, Vascular, Humans, Inflammation, Integrin alpha4beta1, Intercellular Adhesion Molecule-1, Lymphocyte Function-Associated Antigen-1, Macrophages, Peritoneal, Mice, Mice, Knockout, Oncogene Protein v-cbl, Signal Transduction, Ubiquitin-Protein Ligases
Blood
Date: Apr. 01, 2008
PubMed ID: 18239087
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