JAM-L-mediated leukocyte adhesion to endothelial cells is regulated in cis by alpha4beta1 integrin activation

J Cell Biol. 2008 Dec 15;183(6):1159-73. doi: 10.1083/jcb.200805061. Epub 2008 Dec 8.

Abstract

Junctional adhesion molecules (JAMs) are endothelial and epithelial adhesion molecules involved in the recruitment of circulating leukocytes to inflammatory sites. We show here that JAM-L, a protein related to the JAM family, is restricted to leukocytes and promotes their adhesion to endothelial cells. Cis dimerization of JAM-L is required to engage in heterophilic interactions with its cognate counter-receptor CAR (coxsackie and adenovirus receptor). Interestingly, JAM-L expressed on neutrophils binds CAR independently of integrin activation. However, on resting monocytes and T lymphocytes, which express the integrin VLA-4, JAM-L molecules engage in complexes with VLA-4 and mainly accumulate in their monomeric form. Integrin activation is required for the dissociation of JAM-L-VLA-4 complexes and the accumulation of functional JAM-L dimers, which indicates that the leukocyte integrin VLA-4 controls JAM-L function in cis by controlling its dimerization state. This provides a mechanism through which VLA-4 and JAM-L functions are coordinately regulated, allowing JAM-L to strengthen integrin-dependent adhesion of leukocytes to endothelial cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion
  • Cell Adhesion Molecules / metabolism*
  • Cell Line
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Dimerization
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism*
  • Humans
  • Immunologic Memory
  • Integrin alpha4beta1 / metabolism*
  • Leukocytes / cytology*
  • Leukocytes / metabolism*
  • Monocytes / cytology
  • Monocytes / metabolism
  • Neutrophils / cytology
  • Neutrophils / metabolism
  • Protein Binding
  • Receptors, Virus / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism

Substances

  • CLMP protein, human
  • Cell Adhesion Molecules
  • Coxsackie and Adenovirus Receptor-Like Membrane Protein
  • Integrin alpha4beta1
  • JAML protein, human
  • Receptors, Virus