The laminin receptor modulates granulocyte-macrophage colony-stimulating factor receptor complex formation and modulates its signaling

Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14000-5. doi: 10.1073/pnas.2334584100. Epub 2003 Nov 12.

Abstract

Basement membrane matrix proteins are known to up-regulate granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling in neutrophils and mononuclear phagocytes, but the mechanisms involved are poorly understood. We used the intracellular portion of the alpha subunit of the GM-CSF receptor (alphaGMR) to search for interacting proteins and identified the 67-kDa laminin receptor (LR), a nonintegrin matrix protein receptor expressed in several types of host defense cells and certain tumors, as a binding partner. LR was found to interact with the beta subunit of the GMR (betaGMR) as well. Whereas GM-CSF functions by engaging the alphaGMR and betaGMR into receptor complexes, LR inhibited GM-CSF-induced receptor complex formation. Laminin and fibronectin binding to LR was found to prevent the binding of betaGMR to LR and relieved the LR inhibition of GMR. These findings provide a mechanistic basis for enhancing host defense cell responsiveness to GM-CSF at transendothelial migration sites while suppressing it in circulation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Binding Sites
  • Cell Line
  • DNA, Complementary / genetics
  • Fibronectins / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Laminin / metabolism
  • Macromolecular Substances
  • Models, Molecular
  • Molecular Weight
  • Neutrophils / metabolism
  • Protein Structure, Tertiary
  • Protein Subunits
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / chemistry
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Receptors, Laminin / chemistry
  • Receptors, Laminin / metabolism*
  • Signal Transduction

Substances

  • DNA, Complementary
  • Fibronectins
  • Laminin
  • Macromolecular Substances
  • Protein Subunits
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Receptors, Laminin
  • Granulocyte-Macrophage Colony-Stimulating Factor