Download Syndecan Regulation of Adhesion in Normal and Transformed Cells

Syndecan Regulation of Adhesion in Normal and Transformed Cells
John R. Couchman
Department of Biomedical Sciences, University of Copenhagen, Biocenter, Ole Maaloes
Vej 5, 2200 Copenhagen N, Denmark. [email protected]
Syndecans are a family of transmembrane proteoglycans, consisting of four members in
mammals. They are present in virtually all nucleated cells, and in many cases, multiple
members of the group may be localized in a single cell type. All possess
glycosaminoglycan chains, usually three or more, located towards the N-terminus of
their type I membrane proteins. As a group they have a long evolutionary history and
multiple roles, but all have cytoplasmic connections to the actin cytoskeleton. Therefore,
it is unsurprising that they can regulate cell adhesion and migration. Syndecan-4
regulates integrin-mediated adhesion, and has direct interactions with -actinin and
indirect regulatory functions through activation of protein kinase C . In combination
these properties support the formation of focal adhesions, organelles of cell-matrix
adhesion in most anchorage-dependent cell types. However, syndecans are also
present in transformed cells, and we have recently examined their roles in breast
carcinoma. Syndecan-1 expression correlates with disease progression and severity,
and is a marker of poor prognosis, particularly when present in the stroma. Syndecan-4
is an independent marker, in fact of better prognosis. Given this, we are investigating
syndecan-4 function in the MDA-MB231 cell line. The proteoglycan localizes to
invadopodia, and its cell surface levels correlate inversely with collagen invasion and
degradation, processes that are dependent on MT1-MMP (MMP14). Syndecan-1 does
not share these features. Moreover, signaling through syndecan-4 core protein seems
less influential than in untransformed cells, but its heparan sulfate chains are critical to
function. Indeed, exogenous heparin and heparan sulfate have pronounced effects on
cell spreading, junction formation and cell migration. Current work is directed to
understanding the molecular basis by which the heparan sulfate chains regulate
mammary carcinoma cell adhesion and indirectly influences MT1-MMP activity.
Keywords: proteoglycan, cell adhesion, signaling
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