Dissociation of Heparan Sulfate and Receptor Binding Domains of Hepatocyte Growth Factor Reveals That Heparan Sulfate-c-Met Interaction Facilitates Signaling

Syndecan-1 is a heparan sulfate proteoglycan expressed on the surface of, and actively shed by, myeloma cells. Hepatocyte growth factor (HGF) is a cytokine produced by myeloma cells. Previous studies have demonstrated elevated levels of syndecan-1 and HGF in the serum of patients with myeloma, both of negative prognostic value for the disease. Here we show that the median concentrations of syndecan-1 (900 ng/mL) and HGF (6 ng/mL) in the marrow compartment of patients with myeloma are highly elevated compared with healthy controls and controls with other diseases. We show that syndecan-1 isolated from the marrow of patients with myeloma seems to exist in an intact form, with glucosaminoglycan chains. Because HGF is a heparan-sulfate binding cytokine, we examined whether it interacted with soluble syndecan-1. In supernatants from myeloma cells in culture as well as in pleural effusions from patients with myeloma, HGF existed in a complex with soluble syndecan-1. Washing myeloma cells with purified soluble syndecan-1 could effectively displace HGF from the cell surface, suggesting that soluble syndecan-1 can act as a carrier for HGF in vivo. Finally, using a sensitive HGF bioassay (interleukin-11 production from the osteosarcoma cell line Saos-2) and intact syndecan-1 isolated from the U-266 myeloma cell line, we found that the presence of high concentrations of syndecan-1 (more than 3 μg/mL) inhibited the HGF effect, whereas lower concentrations potentiated it. HGF is only one of several heparin-binding cytokines associated with myeloma. These data indicate that soluble syndecan-1 may participate in the pathology of myeloma by modulating cytokine activity within the bone marrow.

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Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor.

Molecular and Cellular Biology ◽

10.1128/mcb.12.11.5152 ◽

1992 ◽

Vol 12 (11) ◽

pp. 5152-5158 ◽

Cited By ~ 203

Author(s):

S Rong ◽

M Bodescot ◽

D Blair ◽

J Dunn ◽

T Nakamura ◽

...

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Growth Factor Receptor ◽

Activation Mechanism ◽

3T3 Cells ◽

Transformation Mechanism ◽

Binding Domains ◽

Nih 3T3 ◽

Hepatocyte Growth ◽

Nih 3T3 Cells

The met proto-oncogene is the tyrosine kinase growth factor receptor for hepatocyte growth factor/scatter factor (HGF/SF). It was previously shown that, like the oncogenic tpr-met, the mouse met proto-oncogene transforms NIH 3T3 cells. We have established NIH 3T3 cells stably expressing both human (Methu) and mouse (Metmu) met proto-oncogene products. The protein products are properly processed and appear on the cell surface. NIH 3T3 cells express endogenous mouse HGF/SF mRNA, suggesting an autocrine activation mechanism for transformation by Metmu. However, the tumor-forming activity of Methu in NIH 3T3 cells is very low compared with that of Metmu, but efficient tumorigenesis occurs when Methu and HGF/SFhu are coexpressed. These results are consistent with an autocrine transformation mechanism and suggest further that the endogenous murine factor inefficiently activates the tumorigenic potential of Methu. The tumorigenicity observed with reciprocal chimeric human and mouse receptors that exchange external ligand-binding domains supports this conclusion. We also show that HGF/SFhu expressed in NIH 3T3 cells produces tumors in nude mice.

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Characterization of Heparan Sulfate Oligosaccharides That Bind to Hepatocyte Growth Factor

Journal of Biological Chemistry ◽

10.1074/jbc.270.49.29586 ◽

1995 ◽

Vol 270 (49) ◽

pp. 29586-29593 ◽

Cited By ~ 90

Author(s):

Satoko Ashikari ◽

Hiroko Habuchi ◽

Koji Kimata

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Heparan Sulfate ◽

Heparan Sulfate Oligosaccharides ◽

Hepatocyte Growth

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

Blood ◽

10.1182/blood.v99.4.1405 ◽

2002 ◽

Vol 99 (4) ◽

pp. 1405-1410 ◽

Cited By ~ 184

Author(s):

Patrick W. B. Derksen ◽

Robert M. J. Keehnen ◽

Ludo M. Evers ◽

Marinus H. J. van Oers ◽

Marcel Spaargaren ◽

...

Keyword(s):

Multiple Myeloma ◽

Growth Factor ◽

Protein Kinase ◽

Hepatocyte Growth Factor ◽

Heparan Sulfate ◽

Growth Regulation ◽

Plasma Cells ◽

Mitogen Activated Protein Kinase ◽

Growth Factor Signaling ◽

Hepatocyte Growth

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.

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Interaction of hepatocyte growth factor with heparan sulfate. Elucidation of the major heparan sulfate structural determinants

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)78113-7 ◽

1994 ◽

Vol 269 (15) ◽

pp. 11216-11223

Author(s):

M. Lyon ◽

J.A. Deakin ◽

K. Mizuno ◽

T. Nakamura ◽

J.T. Gallagher

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Heparan Sulfate ◽

Structural Determinants ◽

Hepatocyte Growth

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Heparin Modulates the Receptor-Binding and Mitogenic Activity of Hepatocyte Growth Factor on Hepatocytes

Experimental Cell Research ◽

10.1006/excr.1993.1316 ◽

1993 ◽

Vol 209 (2) ◽

pp. 317-324 ◽

Cited By ~ 54

Author(s):

Daiji Naka ◽

Takehisa Ishii ◽

Takeshi Shimomura ◽

Tadashi Hishida ◽

Hiroto Hara

Keyword(s):

Growth Factor ◽

Hepatocyte Growth Factor ◽

Receptor Binding ◽

Mitogenic Activity ◽

Hepatocyte Growth

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Heparan Sulfate-modified CD44 Promotes Hepatocyte Growth Factor/Scatter Factor-induced Signal Transduction through the Receptor Tyrosine Kinase c-Met

Journal of Biological Chemistry ◽

10.1074/jbc.274.10.6499 ◽

1999 ◽

Vol 274 (10) ◽

pp. 6499-6506 ◽

Cited By ~ 159

Author(s):

Robbert van der Voort ◽

Taher E. I. Taher ◽

Vera J. M. Wielenga ◽

Marcel Spaargaren ◽

Remko Prevo ◽

...

Keyword(s):

Signal Transduction ◽

Growth Factor ◽

Hepatocyte Growth Factor ◽

Tyrosine Kinase ◽

Heparan Sulfate ◽

Receptor Tyrosine Kinase ◽

Scatter Factor ◽

Kinase C ◽

Induced Signal ◽

Hepatocyte Growth

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Alveolar heparan sulfate shedding impedes recovery from bleomycin-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00063.2020 ◽

2020 ◽

Vol 318 (6) ◽

pp. L1198-L1210 ◽

Cited By ~ 3

Author(s):

W. B. LaRivière ◽

S. Liao ◽

S. A. McMurtry ◽

K. Oshima ◽

X. Han ◽

...

Keyword(s):

Growth Factor ◽

Lung Injury ◽

Hepatocyte Growth Factor ◽

Heparan Sulfate ◽

Growth Factor Signaling ◽

Pulmonary Epithelium ◽

Lung Dysfunction ◽

Air Space ◽

The Impact ◽

Hepatocyte Growth

The pulmonary epithelial glycocalyx, an anionic cell surface layer enriched in glycosaminoglycans such as heparan sulfate and chondroitin sulfate, contributes to the alveolar barrier. Direct injury to the pulmonary epithelium induces shedding of heparan sulfate into the air space; the impact of this shedding on recovery after lung injury is unknown. Using mass spectrometry, we found that heparan sulfate was shed into the air space for up to 3 wk after intratracheal bleomycin-induced lung injury and coincided with induction of matrix metalloproteinases (MMPs), including MMP2. Delayed inhibition of metalloproteinases, beginning 7 days after bleomycin using the nonspecific MMP inhibitor doxycycline, attenuated heparan sulfate shedding and improved lung function, suggesting that heparan sulfate shedding may impair lung recovery. While we also observed an increase in air space heparanase activity after bleomycin, pharmacological and transgenic inhibition of heparanase in vivo failed to attenuate heparan sulfate shedding or protect against bleomycin-induced lung injury. However, experimental augmentation of airway heparanase activity significantly worsened post-bleomycin outcomes, confirming the importance of epithelial glycocalyx integrity to lung recovery. We hypothesized that MMP-associated heparan sulfate shedding contributed to delayed lung recovery, in part, by the release of large, highly sulfated fragments that sequestered lung-reparative growth factors such as hepatocyte growth factor. In vitro, heparan sulfate bound hepatocyte growth factor and attenuated growth factor signaling, suggesting that heparan sulfate shed into the air space after injury may directly impair lung repair. Accordingly, administration of exogenous heparan sulfate to mice after bleomycin injury increased the likelihood of death due to severe lung dysfunction. Together, our findings demonstrate that alveolar epithelial heparan sulfate shedding impedes lung recovery after bleomycin.

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