Growth factor-induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells.
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.
Ding
Kan
K
Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697.
Lopez-Burks
Martha
M
Sánchez-Duran
José Antonio
JA
Korc
Murray
M
Lander
Arthur D
AD
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D018450:Disease Progression; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry; D006801:Humans; D020935:MAP Kinase Signaling System; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism*; D053668:Syndecan-1; D053667:Syndecans; D013997:Time Factors; D014162:Transfection; D014357:Trypsin / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation
D016895:Culture Media, Serum-Free; D004247:DNA; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D006025:Glycosaminoglycans; D006133:Growth Substances; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D020783:Matrix Metalloproteinase 7; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D053668:Syndecan-1; D053667:Syndecans; D014357:Trypsin; C508241:SDC1 protein, human