Modulation of CD11b/CD18 adhesive activity by its extracellular, membrane-proximal regions.
The integrin receptor CD11b/CD18 is normally kept in a low adhesive state and can be activated by many different agents. However, the mechanism underlying receptor activation is not yet fully understood. We hypothesized that the extracellular, membrane-proximal regions of CD11b/CD18 are critically involved in modulation of its adhesive functions. To test our hypothesis, we perturbed the extracellular, membrane-proximal regions of individual CD11b and CD18 subunits and studied their effect on ligand binding, receptor clustering, and lipid raft association. We report here three major findings: 1) perturbation of the extracellular, membrane-proximal region of either subunit leads to enhanced adhesion, caused by changes in receptor conformation, but not the state of receptor clustering or lipid raft association; 2) the CD11b subunit plays a more important role in confining the receptor in an inactive state; and 3) upon modification of the extracellular, membrane-proximal region, the mutant CD11b/CD18 acquires the ability to respond to stimulation by "inside-out" signaling. Our results suggest that the extracellular, membrane-proximal region of the receptor plays an important role in integrin activation and therefore could be targeted by certain cell surface proteins as a conduit to control the integrin "inside-out" signaling process.
Xiong
Yu-Mei
YM
Department of Vascular Biology, American Red Cross Holland Laboratory, Rockville, MD 20855, USA.
Chen
Jian
J
Zhang
Li
L
D000595:Amino Acid Sequence; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D018821:CD18 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics; D005110:Extracellular Space / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D008024:Ligands; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D017434:Protein Structure, Tertiary / Q000235:genetics; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection
D039481:CD11b Antigen; D018821:CD18 Antigens; D008024:Ligands; D021122:Protein Subunits