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Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma.

Heparan sulfate proteoglycans (HSPGs) play a crucial role in growth regulation by assembling signaling complexes and presenting growth factors to their cognate receptors. Within the immune system, expression of the HSPG syndecan-1 (CD138) is characteristic of terminally differentiated B cells, ie, plasma cells, and their malignant counterpart, multiple myeloma (MM). This study explored the hypothesis that syndecan-1 might promote growth factor signaling and tumor growth in MM. For this purpose, the interaction was studied between syndecan-1 and hepatocyte growth factor (HGF), a putative paracrine and autocrine regulator of MM growth. The study demonstrates that syndecan-1 is capable of binding HGF and that this growth factor is indeed a potent stimulator of MM survival and proliferation. Importantly, the interaction of HGF with heparan sulfate moieties on syndecan-1 strongly promotes HGF-mediated signaling, resulting in enhanced activation of Met, the receptor tyrosine kinase for HGF. Moreover, HGF binding to syndecan-1 promotes activation of the phosphatidylinositol 3-kinase/protein kinase B and RAS/mitogen-activated protein kinase pathways, signaling routes that have been implicated in the regulation of cell survival and proliferation, respectively. These results identify syndecan-1 as a functional coreceptor for HGF that promotes HGF/Met signaling in MM cells, thus suggesting a novel function for syndecan-1 in MM tumorigenesis.

Pubmed ID: 11830493

Authors

  • Derksen PW
  • Keehnen RM
  • Evers LM
  • van Oers MH
  • Spaargaren M
  • Pals ST

Journal

Blood

Publication Data

February 15, 2002

Associated Grants

None

Mesh Terms

  • Cell Division
  • Enzyme Activation
  • Hepatocyte Growth Factor
  • Humans
  • MAP Kinase Signaling System
  • Membrane Glycoproteins
  • Multiple Myeloma
  • Phosphatidylinositol 3-Kinases
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Proteoglycans
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-met
  • Signal Transduction
  • Syndecan-1
  • Syndecans
  • Transfection
  • Tumor Cells, Cultured
  • ras Proteins