Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 358, Issue 1, Pages 233-240Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2007.04.100
Keywords
chemokines; metalloprotemases; shedding; secretases; regulated intramembrane proteolysis; cell migration; inflammation
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The chemokines CX3CL1/Fractalkine and CXCL16 are expressed as transmembrane molecules and can mediate cell-cell-adhesion. By proteolytic processing, CX3CL1 and CXCL16 are released from the cell surface by proteolytic shedding resulting in the generation of soluble chemoattractants. This ectodomain release is mediated by the alpha-secretase-like activity of the two disintegrins and metalloproteinases ADAM10 and ADAM17. Using CX3CL1 and CXCL16 constructs C-terminally fused to two Z-domains of Protein A (2Z-tag) we detect C-terminal fragments (CTFs) of both chemokines resulting from ADAM10-mediated cleavages at multiple sites as examined by inhibitor studies. Further-more, inhibitor studies as well as genetic studies using presenilin 1/2-deficient cell lines suggest the involvement of gamma-secretase- but not-beta-secretase-like activity in the processing of transmembrane chemokines. The combination of alpha- and gamma-secretase and proteasomal inhibitors points towards a sequential processing of transmembrane chemokines by first ADAM10 and then gamma-secretases and possible further degradation. This proteolytic processing cascade of transmembrane chemokines is similar to that described for Notch and E-cadherin where CTFs generated by gamma-secretase serve as intracellular, signal transmitters. (c) 2007 Elsevier Inc. All rights reserved.
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