Emerging roles for ectodomain shedding in the regulation of inflammatory responses.
The multistep model of leukocyte recruitment to sites of inflammation has helped elucidate specific molecular cues for each of the individual steps. However, it is less clear how cells transition between the different steps and how the complex interactions are coordinately regulated. Once a leukocyte sticks to the endothelium, it only takes a few minutes to reach the subendothelial basement membrane, so the transitions and regulatory mechanisms must be rapid. We put forward the hypothesis that proteolytic shedding of cell surface proteins provides a mechanism to aid in the rapid transition of cells and coordinate the complex, multistep process of leukocyte recruitment in response to inflammatory stimuli. Support for this hypothesis is provided from analyses of disease states and from studies with protease inhibitors and genetically engineered mutations that prevent "ectodomain shedding" of cell surface proteins and consequently perturb the inflammatory response.
Garton
Kyle J
KJ
Department of Pathology, University of Washington, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104-2499, USA.
Gough
Peter J
PJ
Raines
Elaine W
EW
D051722:ADAM Proteins / Q000502:physiology; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001485:Basement Membrane / Q000502:physiology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018925:Chemokines / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D010450:Endopeptidases / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology*; D007962:Leukocytes / Q000502:physiology*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010447:Peptide Hydrolases / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017434:Protein Structure, Tertiary; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D019087:Selectins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015815:Cell Adhesion Molecules; D018925:Chemokines; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D019087:Selectins; D014409:Tumor Necrosis Factor-alpha; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D000072198:ADAM17 Protein