Differential processing of stromal-derived factor-1α and stromal-derived factor-1β explains functional diversity

Abstract

The chemokine stromal-derived factor-1 (SDF-1), which is constitutively expressed in most tissues as SDF-1alpha and SDF-1beta resulting from alternative gene splicing, regulates hematopoiesis, lymphocyte homing, B-lineage cell growth, and angiogenesis. Because SDF-1alpha and SDF-1beta are constitutively and ubiquitously expressed, their degradation must serve an important regulatory role. Here we show that SDF-1alpha and SDF-1beta are secreted as full-length molecules. When exposed to human serum, full-length SDF-1alpha (1-68) undergoes processing first at the COOH terminus to produce SDF-1alpha 1-67 and then at the NH2 terminus to produce SDF-1alpha 3-67. By contrast, full-length SDF-1beta (1-72) is processed only at the NH2 terminus to produce SDF-1beta 3-72. CD26/dipeptidyl peptidase is responsible for serum cleavage of SDF-1alpha and SDF-1beta at the NH2 terminus. Serum processing of SDF-1alpha at the COOH terminus, which has not been previously reported, reduces the ability of the polypeptide to bind to heparin and to cells and to stimulate B-cell proliferation and chemotaxis. The additional processing at the NH2 terminus renders both forms of SDF-1 unable to bind to heparin and to activate cells. The differential processing of SDF-1alpha and SDF-1beta provides biologic significance to the existence of 2 splice forms of the chemokine and adds a tool to precisely regulate SDF-1's biologic activity by changes in specific activity.

Angiogenic effects of stromal cell-derived factor-1 (SDF-1/CXCL12) variants in vitro and the in vivo expressions of CXCL12 variants and CXCR4 in human critical leg ischemia

“…This difference in activity could possibly be attributed to the differential processing of these proteins, which reduced the affinity of CXCL12␣ to bind to cells. 29 In addition, a previous study 30 showed different C-termini of CXCL12 variants may contain important molecular determinants for differences in biologic functions. This may affect binding of CXCL12 to cells either via the receptor CXCR4 or heparin sulphate, a glycosaminoglycan found ubiquitously in cell surfaces.…”

Overview of the mechanisms regulating chemokine activity and availability

“…This gives rise to six protein isoforms with shared NH 2 -termini (amino acids 1 to 68 are identical) but dissimilar COOH-termini (in length and composition). These isoforms, containing 68, 72, 98, 119, 69 and 79 amino acids respectively, display different tissue distribution patterns, different susceptibility to COOH-terminal proteolytic cleavage, different CXCR4 binding and signaling capacities and different anti-HIV activities [63][64][65][66][67][68]. Of note are their explicit variation in GAG binding affinity.…”

Inhibition of SDF-1/CXCR4-induced epithelial–mesenchymal transition by kisspeptin-10

“…It was shown that neutralization of SDF-1 in a mouse xenograft model significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung [3]. By alternate splicing SDF-1 is produced in the two isoforms SDF-1a and SDF-1b [7].…”