Syndecan-1 is a
heparan sulfate proteoglycan expressed by endothelial and epithelial cells and involved in wound healing and
tumor growth. Surface-expressed
syndecan-1 undergoes proteolytic shedding leading to the release of the soluble N-terminal ectodomain from a transmembrane C-terminal fragment (tCTF). We show that the
disintegrin and
metalloproteinase (ADAM) 17 generates a
syndecan-1 tCTF, which can then undergo further intra-membrane proteolysis by γ-
secretase. Scratch-induced
wound closure of cultured lung epithelial A549
tumor cells associates with increased
syndecan-1 cleavage as evidenced by the release of shed
syndecan-1 ectodomain and enhanced generation of the tCTF. Both
wound closure and the associated
syndecan-1 shedding can be suppressed by inhibition of ADAM family
proteases. Cell proliferation, migration and invasion into
matrigel as well as several signaling pathways implicated in these responses are suppressed by silencing of
syndecan-1. These defects of
syndecan-1 deficient cells can be overcome by overexpression of
syndecan-1 tCTF or a corresponding tCTF of
syndecan-4 but not by overexpression of a tCTF lacking the transmembrane domain. Finally, lung
metastasis formation of A549 cells in SCID mice was found to be dependent on
syndecan-1, and the presence of
syndecan-1 tCTF was sufficient for this activity. Thus, the
syndecan-1 tCTF by itself is capable of mediating critical syndecan-1-dependent functions in cell proliferation, migration, invasion and
metastasis formation and therefore can replace full length
syndecan-1 in the situation of increased
syndecan-1 shedding during cell migration and
tumor formation.