Natural hepatocyte growth factor (HGF) from human serum and a bound form of recombinant HGF with heparan sulfate are indistinguishable in their physicochemical properties

1998 ◽  
Vol 23 (3) ◽  
pp. 227-235 ◽  
Author(s):  
Kazuki Yano ◽  
Eisuke Tsuda ◽  
Masatsugu Ueda ◽  
Kanji Higashio
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Physicochemical Properties ◽  
Heparan Sulfate ◽  
Human Serum ◽  
Hepatocyte Growth

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

2001 ◽  
Vol 276 (35) ◽  
pp. 32977-32983 ◽  
Author(s):  
Jeffrey S. Rubin ◽  
Regina M. Day ◽  
Diane Breckenridge ◽  
Nese Atabey ◽  
William G. Taylor ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Receptor Binding ◽  
Binding Domains ◽  
Hepatocyte Growth

High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3139-3146 ◽  
Author(s):  
Carina Seidel ◽  
Magne Børset ◽  
Øyvind Hjertner ◽  
Dianjun Cao ◽  
Niels Abildgaard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Cell Line ◽  
Osteosarcoma Cell ◽  
Heparin Binding ◽  
Myeloma Cells ◽  
Hepatocyte Growth

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.

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

Blood ◽  
2002 ◽  
Vol 99 (4) ◽  
pp. 1405-1410 ◽  
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.

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

2020 ◽  
Vol 318 (6) ◽  
pp. L1198-L1210 ◽  
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.

Abstract B228: A hepatocyte growth factor antagonist engineered by targeted disruption of heparan sulfate binding

2009 ◽  
Author(s):  
Fabiola Cecchi ◽  
Deborah Pajalunga ◽  
Daniel Rabe ◽  
Andrew C. Fowler ◽  
Nicholas MacDonald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Targeted Disruption ◽  
Hepatocyte Growth ◽  
Factor Antagonist

High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3139-3146 ◽  
Author(s):  
Carina Seidel ◽  
Magne Børset ◽  
Øyvind Hjertner ◽  
Dianjun Cao ◽  
Niels Abildgaard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Cell Line ◽  
Osteosarcoma Cell ◽  
Heparin Binding ◽  
Myeloma Cells ◽  
Hepatocyte Growth

Abstract 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.

scholarly journals Isolation and Characterization of a Chinese Hamster Ovary Heparan Sulfate Cell Mutant Defective in Both Met Receptor Binding and Hepatocyte Growth Factor NK1/Met Signaling

2018 ◽  
Vol 48 (4) ◽  
pp. 1480-1491 ◽  
Author(s):  
Tong Cao ◽  
Jing Pan ◽  
Xiulian Li ◽  
Yanli He ◽  
Yifei Jiang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Recombinant Protein ◽  
Cell Surface ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Model Systems ◽  
Physiological Conditions ◽  
Negative Cell ◽  
Cell Clones ◽  
Hepatocyte Growth

Background/Aims: The up-regulation of hepatocyte growth factor/receptor, HGF/Met, signal transduction is observed in most of human cancers. Specific heparan sulfate structures enhance the HGF/Met signaling at both cell and animal-based model systems. Biochemical studies indicate that heparan sulfate interacts with HGF and a natural occurring splicing variant NK1 of HGF with similar affinity. However, it is currently unknown if cell surface heparan sulfate binds to Met at physiological conditions and if specific cell surface heparan sulfate structures are required for effective HGF/Met or NK1/Met signaling. Methods: An established flow sorting strategy was used to isolate a soluble Met recombinant protein-binding positive or negative CHO cell clones different only in specific heparan sulfate structures. The cell surface bindings were imaged by confocal microscopy and flow cytometry analysis. Glucosamine vs. galactosamine contents from media-, cell surface-, and cell association glycosaminoglycans were quantified by HPLC. 35S-sulfate labeled glycosaminoglycans were characterized by anion exchange and size-exclusion HPLC. Heparan sulfate disaccharide compositions were determined by HPLC-MS analysis. Western blot analyses of MAPK-p42/44 were used to monitor HGF- and NK1-facillated Met signaling. Results: CHO-Positive but not CHO-Negative cell surface heparan sulfate bound to Met recombinant protein and HGF/NK1 further promoted the binding. Overall glycosaminoglycan analysis results indicated that the CHO-Negative cells had reduced amount of heparan sulfate, shorter chain length, and less 6-O-sulfated disaccharides compared to that of CHO-Positive cells. Moreover, CHO-Negative cells were defective in NK1/Met but not HGF/Met signaling. Conclusions: This study demonstrated that soluble Met recombinant protein bound to cell surface HS at physiological conditions and a Met /HGF or NK1/HS ternary signaling complex might be involved in Met signaling. Shorter HS chains and reduced 6-O-sulfation might be responsible for reduced Met binding and the diminished NK1-initiated signaling in the CHO-Negative cells. The unique CHO-Positive and CHO-Negative cell clones established in current study should be effective tools for studying the role of specific glycosaminoglycan structures in regulating Met signaling. Such knowledge should be useful in developing glycosaminoglycan-based compounds that target HGF/Met signaling.

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