Mapping of matrix metalloproteinase cleavage sites on syndecan-1 and syndecan-4 ectodomains

TY - JOUR

T1 - Mapping of matrix metalloproteinase cleavage sites on syndecan-1 and syndecan-4 ectodomains

AU - Manon-Jensen, Tina

AU - Multhaupt, Hinke A B

AU - Couchman, John R

N1 - © 2013 The Authors Journal compilation © 2013 FEBS.

PY - 2013/5

Y1 - 2013/5

N2 - 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. Syndecans are transmembrane signalling proteoglycans whose glycosaminoglycan chains and core proteins regulate cell behaviour. Syndecan ectodomains are shed from cell surfaces by several classes of enzymes, notably metalloproteinases, but the sites and significance of cleavage remain poorly known. We have mapped multiple cleavage sites for several tumour-associated metalloproteinases in syndecan-1 and -4 ectodomains and identify sub-domains of high proteinase sensitivity.

AB - 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. Syndecans are transmembrane signalling proteoglycans whose glycosaminoglycan chains and core proteins regulate cell behaviour. Syndecan ectodomains are shed from cell surfaces by several classes of enzymes, notably metalloproteinases, but the sites and significance of cleavage remain poorly known. We have mapped multiple cleavage sites for several tumour-associated metalloproteinases in syndecan-1 and -4 ectodomains and identify sub-domains of high proteinase sensitivity.

U2 - 10.1111/febs.12174

DO - 10.1111/febs.12174

M3 - Journal article

C2 - 23384311

SN - 1742-464X

VL - 280

SP - 2320

EP - 2331

JO - F E B S Journal

JF - F E B S Journal

IS - 10

ER -