Tumor necrosis factor-alpha-converting enzyme mediates the inducible cleavage of fractalkine.
Fractalkine (FK, CX3CL1) is a novel multidomain protein expressed on the surface of endothelial cells. As a full-length transmembrane protein, FK binds cells expressing CX3CR1, its cognate receptor, with high affinity. Proteolytic cleavage of FK releases a soluble form that is a potent chemoattractant for monocytes, T cells, and natural killer cells. Activation of protein kinase C dramatically increases the rate of this cleavage. Regulation of FK cleavage is critical for maintaining the balance between the immobilized and soluble forms, but the protease responsible has not been identified. Here we report that tumor necrosis factor-alpha-converting enzyme (TACE) is primarily responsible for the inducible cleavage of FK. After transfection into host cells, the proteolytic cleavage of FK was blocked by TACE-specific inhibitors and was not detected in cells genetically altered to remove TACE activity. In contrast, the constitutive cleavage of FK was not mediated by TACE and proceeded normally in TACE-null fibroblasts. We conclude that TACE is primarily responsible for the inducible cleavage of FK. These studies identify a potentially important link between local generation of potent cytokines and control of the balance between the cell adhesion and chemotactic properties of FK.
Tsou
C L
CL
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141-9100, USA.
Haskell
C A
CA
Charo
I F
IF
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002448:Cell Adhesion; D002460:Cell Line; D054428:Chemokine CX3CL1; D018925:Chemokines / Q000378:metabolism; D020523:Chemokines, CX3C / Q000378:metabolism*; D002633:Chemotaxis; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism*; D010618:Phenanthrolines / Q000494:pharmacology; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D054428:Chemokine CX3CL1; D018925:Chemokines; D020523:Chemokines, CX3C; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D010618:Phenanthrolines; D011493:Protein Kinase C; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; D013755:Tetradecanoylphorbol Acetate