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J. Cell Biol. 171 (4): 729-738

Copyright © 2005 by the Rockefeller University Press.


Article

Growth factor–induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells

Kan Ding1, Martha Lopez-Burks1, José Antonio Sánchez-Duran1, Murray Korc2, , and Arthur D. Lander1

1 Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697
2 Department of Medicine, Dartmouth Medical School, Hanover, NH 03755

Correspondence to Arthur D. Lander: adlander{at}uci.edu

Abstract: The cell surface heparan sulfate proteoglycan (HSPG) glypican-1 is up-regulated by pancreatic and breast cancer cells, and its removal renders such cells insensitive to many growth factors. We sought to explain why the cell surface HSPG syndecan-1, which is also up-regulated by these cells and is a known growth factor coreceptor, does not compensate for glypican-1 loss. We show that the initial responses of these cells to the growth factor FGF2 are not glypican dependent, but they become so over time as FGF2 induces shedding of syndecan-1. Manipulations that retain syndecan-1 on the cell surface make long-term FGF2 responses glypican independent, whereas those that trigger syndecan-1 shedding make initial FGF2 responses glypican dependent. We further show that syndecan-1 shedding is mediated by matrix metalloproteinase-7 (MMP7), which, being anchored to cells by HSPGs, also causes its own release in a complex with syndecan-1 ectodomains. These results support a specific role for shed syndecan-1 or MMP7–syndecan-1 complexes in tumor progression and add to accumulating evidence that syndecans and glypicans have nonequivalent functions in vivo.

Abbreviations used in this paper: GAG, glycosaminoglycan; GPI, glycosylphosphatidylinositol; HB-EGF, heparin-binding EGF-like growth factor; HGF, hepatocyte growth factor; HSPG, heparan sulfate proteoglycan; MMP, matrix metalloproteinase; PIPLC, phosphoinositide-specific PLC.


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