Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases
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Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases. / Schulte, A; Schulz, B; Andrzejewski, M G; Hundhausen, C; Mletzko, S; Achilles, J; Reiss, K; Paliga, K; Weber, C; John, S Rose; Ludwig, A.
in: BIOCHEM BIOPH RES CO, Jahrgang 358, Nr. 1, 22.06.2007, S. 233-40.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Sequential processing of the transmembrane chemokines CX3CL1 and CXCL16 by alpha- and gamma-secretases
AU - Schulte, A
AU - Schulz, B
AU - Andrzejewski, M G
AU - Hundhausen, C
AU - Mletzko, S
AU - Achilles, J
AU - Reiss, K
AU - Paliga, K
AU - Weber, C
AU - John, S Rose
AU - Ludwig, A
PY - 2007/6/22
Y1 - 2007/6/22
N2 - 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. Furthermore, 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.
AB - 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. Furthermore, 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.
KW - ADAM Proteins
KW - Amyloid Precursor Protein Secretases
KW - Cell Line
KW - Chemokine CX3CL1
KW - Chemokines, CX3C
KW - Chemokines, CXC
KW - Cloning, Molecular
KW - Humans
KW - Membrane Proteins
KW - Presenilin-1
KW - Presenilin-2
KW - Proteasome Endopeptidase Complex
KW - Protein Structure, Tertiary
KW - Receptors, Scavenger
U2 - 10.1016/j.bbrc.2007.04.100
DO - 10.1016/j.bbrc.2007.04.100
M3 - SCORING: Journal article
C2 - 17467666
VL - 358
SP - 233
EP - 240
JO - BIOCHEM BIOPH RES CO
JF - BIOCHEM BIOPH RES CO
SN - 0006-291X
IS - 1
ER -