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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.

Pubmed ID: 18239087

Authors

  • Choi EY
  • Orlova VV
  • Fagerholm SC
  • Nurmi SM
  • Zhang L
  • Ballantyne CM
  • Gahmberg CG
  • Chavakis T

Journal

Blood

Publication Data

April 1, 2008

Associated Grants

  • Agency: NHLBI NIH HHS, Id: P01 HL054710
  • Agency: NHLBI NIH HHS, Id: R01 HL061589

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