title: Chemokine-triggered leukocyte arrest: force-regulated bi-directional integrin activation in quantal adhesive contacts.
abstract: The arrest of rolling leukocytes on target vascular beds is mediated by specialized leukocyte integrins and their endothelial ligands. In the circulation, these integrins are generally maintained as inactive 'clasped' heterodimers. Encounter by leukocytes of specialized endothelial-presented chemoattractants termed arrest chemokines drive these integrins to undergo force-regulated biochemical conformational changes in response to signals from chemokine-stimulated Gi-protein coupled receptors (GPCRs) and actin remodeling Rho GTPases. To arrest rolling leukocytes, integrin:ligand bonds must undergo stabilization by several orders of magnitude within quantal submicron contacts that consist of discrete integrin:ligand bonds. We present a unifying three step model for rapid integrin activation by chemokines in the quantal arrest unit, the smallest firm adhesive contact formed by a rolling or a captured leukocyte: integrin extension triggered by talin, integrin headpiece opening driven by surface-immobilized ligand and stabilized by low force, and full heterodimer unclasping requiring integrin tail associations with actin-connected talin and Kindlin-3. Specialized GPCRs and their Gi-protein signaling assemblies drive these and other adaptors to specifically bind integrin cytoplasmic tails possibly in conjunction with de novo actin remodeling, thereby optimizing bi-directional activation of ligand-occupied integrins.
authors: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. ronen.alon@weizmann.ac.il
authors: Ronen
authors: R
authors: Alon
authors: Sara W
authors: SW
authors: Feigelson
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000378:metabolism; D002448:Cell Adhesion; D018925:Chemokines / Q000276:immunology / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D036904:Leukocyte Rolling; D007962:Leukocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D018925:Chemokines; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D020559:Monomeric GTP-Binding Proteins