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SRC-dependent outside-in signalling is a key step in the process of autoregulation of beta2 integrins in

Paola Piccardoni1, Stefano Manarini, Lorenzo Federico

  • 1Laboratory of Vascular Biology and Pharmacology, Consorzio Mario Negri Sud, Via Nazionale 1, 66030, Santa Maria Imbaro, Italy.

The Biochemical Journal
|February 19, 2004
PubMed

Insights

SRC kinases are essential for stabilizing beta2-integrin-mediated adhesion in polymorphonuclear cells (PMN). This outside-in signaling pathway strengthens cell interactions by promoting integrin clustering and F-actin accumulation, crucial for immune responses.

Area of Science:

  • Cellular Biology
  • Immunology
  • Molecular Signaling

Background:

  • Beta2-integrin Mac-1 (macrophage antigen-1) activation is promoted by SRC family kinases (SFKs) like HCK and LYN in human polymorphonuclear cells (PMN).
  • SRC kinase activity is critical for Mac-1-mediated adhesion, suggesting an SRC-dependent outside-in signaling pathway strengthens beta2-integrin-ligand interactions.

Purpose of the Study:

  • To investigate the role of SRC-dependent outside-in signaling in stabilizing beta2-integrin-mediated adhesion.
  • To determine if SRC kinases link high-affinity integrin states to high-avidity cell adhesion.

Main Methods:

  • Utilized monoclonal antibody KIM127 or manganese to induce a high-affinity state in beta2 integrins.
  • Analyzed homotypic PMN adhesion, P-110 phosphorylation, and F-actin accumulation.
  • Employed blocking antibodies, SRC inhibitors, confocal microscopy, and FACS analysis.

Main Results:

  • KIM127 or manganese induced PMN homotypic adhesion and P-110 phosphorylation, processes abolished by SRC inhibitors or blocking antibodies.
  • SRC kinase and actin polymerization blockade prevented activated integrin clustering and F-actin accumulation.
  • SRC-dependent outside-in signaling was also required for interleukin-8-triggered adhesion.

Conclusions:

  • SRC-dependent outside-in signaling, triggered by high-affinity and ligand binding, is necessary for stabilizing beta2-integrin-mediated adhesion.
  • SRC kinases facilitate the transition from high-affinity to high-avidity states by promoting activated integrin clustering.
  • Proline-rich tyrosine kinase-2 is implicated in this signaling pathway.

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