Matrix Metalloproteinase Activity Inactivates the CXC Chemokine Stromal Cell-derived Factor-1*

By Angus Mcquibban, Georgina S. Butler, J. Gong, L. Bendall, C. Power, I. Clark‐Lewis, Christopher M. Overall. Journal of Biological Chemistry, 2001

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Chemokines provide directional cues for leukocyte migration and activation that are essential for normal leukocytic trafficking and for host responses during processes such as inflammation, infection, and cancer. Recently we reported that matrix metalloproteinases (MMPs) modulate the activity of the CC chemokine monocyte chemoattractant protein-3 by selective proteolysis to release the N-terminal tetrapeptide. Here we report the N-terminal processing, also at position 4–5, of the CXC chemokines stromal cell-derived factor (SDF)-1α and β by MMP-2 (gelatinase A). Robustness of the MMP family for chemokine cleavage was revealed from identical cleavage site specificity of MMPs 1, 3, 9, 13, and 14 (MT1-MMP) toward SDF-1; selectivity was indicated by absence of cleavage by MMPs 7 and 8. Efficient cleavage of SDF-1α by MMP-2 is the result of a strong interaction with the MMP hemopexin C domain at an exosite that overlaps the monocyte chemoattractant protein-3 binding site. The association of SDF-1α with different glycosaminoglycans did not inhibit cleavage. MMP cleavage of SDF-1α resulted in loss of binding to its cognate receptor CXCR-4. This was reflected in a loss of chemoattractant activity for CD34+ hematopoietic progenitor stem cells and pre-B cells, and unlike full-length SDF-1α, the MMP-cleaved chemokine was unable to block CXCR-4-dependent human immunodeficiency virus-1 infection of CD4+ cells. These data suggest that MMPs may be important regulatory proteases in attenuating SDF-1 function and point to a deep convergence of two important networks, chemokines and MMPs, to regulate leukocytic activity in vivo.

Subfields: Cancer Research, Immunology and Allergy, Oncology

View Paper: https://www.semanticscholar.org/paper/67ec080ea1beda1a9912dcfb14e3ad50cb8d06a5

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Citations in the corpus

Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. (2002, background): “Reduction of bone marrow SDF-1 levels and CXCR4 upregulation mediate G-CSF-induced mobilization of human and murine stem cells In recent reports proteolytic enzymes, including elastase, cathepsin G, MMP-2, and MMP-9, were found to inactivate SDF-1 by cleaving a few amino acids at the signaling N-ter”
Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation (2007, background): “CXCL12 inactivation is not restricted to MMP-2, as MMP-1, MMP-3, MMP-9, MMP-13, and MMP-14 have been shown to inactivate this chemokine [12].”
New functions for the matrix metalloproteinases in cancer progression (2002, background): “cgi?l=6387">CXCL12 (also known as stromal-cell-derived factor 1; SDF1) is cleaved and inactivated by MMP-1, -3, -9, -13 and -14 (Ref”
Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9) (2002, background): “Signaling via p38 MAPK was also observed to be required to upregulate gelatinase B secretion by both rat glioma cells and human T cells after binding of the chemokines stromal cellderived factor 1α (SDF-1α) and macrophage inflammatory protein 1β (MIP-1β) to their receptors (Misse et al., 2001).”
Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. (2002, methodology): “Figure 2 shows that MCP-1 is cleaved at Ala4-Ile5, designated MCP-1(5-76); by MMP-1; to a lesser extent (20% of total by densitometric analysis) by MMP-3; and to a very minor extent (5% of total) by MMP-8.”
Matrix metalloproteinases as modulators of inflammation. (2008, background): “Several MMPs can cleave the CXC-chemokine ligand 12 (CXCL-12/ SDF-1) in vitro including MMP1, -2, -3, -9, -13, and -14, and MMP cleavage of CXCL-12 results in loss of its ability to bind its cognate receptor, CXCR4 [3].”
Matrix metalloproteinases and the regulation of tissue remodelling (2007, background): “Truncation of macrophage-derived CCL7 by MMP2 and MMP14 results in the formation of peptides that can bind to the CC chemokine receptor and function as antagonist”
Extracellular matrix remodelling: the role of matrix metalloproteinases (2003, background): “Stromal cell-derived factor (SDF-1 also known as CXCL12) undergoes inactivating cleavage by several MMPs, including MMP-1, -3, -9, -13, and -14 [67].”
Gelatinase-mediated migration and invasion of cancer cells. (2005, background): “…yes (Yu and Stamenkovic, 2000) Pro-TNF-α yes yes (Gearing et al., 1994) Pro-urokinase yes (Prager et al., 2003) Stromal cell derived factor (SDF)-1 yes yes (McQuibban et al., 2001) Substance P yes (Backstrom and Tokes, 1995) Troponin yes (Wang et al., 2002) Urokinase receptor yes no (Andolfo et…”
Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells (2006, background): “Proteolytic processing and inactivation of SDF-1 by degrading enzymes such as elastase, cathepsin G, CD26, MT1-MMP and MMP-9 were previously reported as part of the mobilization proces”