Syndecans are transmembrane heparan sulfate proteoglycans with roles in cell 
proliferation, differentiation, adhesion, and migration. They have been 
associated with multiple functions in tumour progression, through their ability 
to interact with a wide range of ligands as well as other receptors, which makes 
them key effectors in the pericellular microenvironment. Extracellular shedding 
of syndecans by tumour-associated matrix metalloproteinases (MMPs) may have an 
important role in tumour progression. Such ectodomain shedding generates soluble 
ectodomains that may function as paracrine or autocrine effectors, or as 
competitive inhibitors of the intact proteoglycan. Tumour-associated MMPs are 
shown here to cleave the ectodomains of human syndecan-1 and syndecan-4. Two 
membrane proximal regions of both syndecan-1 and syndecan-4 are favoured MMP 
cleavage sites, six and 15 residues from the transmembrane domain. Other sites 
are 35-40 residues C-terminal from the heparan sulfate chain substitution sites 
in both syndecans. The MT1-MMP cleavage sites in syndecan-1 and syndecan-4 were 
confirmed by site-directed mutagenesis. These findings provide insights into the 
characteristics of syndecan shedding.