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      Heparin‐binding Epidermal Growth Factor‐like Growth Factor: p91 Activation, Induction of Plasminogen Activator/Plasminogen Activator Inhibitor, and Tubular Morphogenesis in Human Microvascular Endothelial Cells

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          Abstract

          Epidermal growth factor (EGF) or transforming growth factor‐α (TGF‐α) stimulates cell migration, proliferation and the formation of tube‐like structures of human microvascular endothelial cells in culture. Heparin‐binding EGF‐like growth factor (HB‐EGF), which shows 35% homology with EGF/ TGF‐α, is a member of the EGF family, and it is ubiquitous in many tissues and organs. We examined whether or not HB‐EGF induced angiogenic responses in human microvascular endothelial cells. HB‐EGF inhibited the binding of 125I‐EGF to the EGF receptor and induced autophosphorylation of the receptor on endothelial cells. Exogenous HB‐EGF induced the loss of more than 70% of the EGF receptor from the cell surface within 30 min, with similar kinetics to that of EGF. The level of c‐ fos mRNA markedly increased at 30 min in response to HB‐EGF as well as EGF. A gel shift assay demonstrated the activation of the transcription factor p91 by HB‐EGF and EGF. This factor directly interacts with the EGF receptor and mediates the activation of c‐ fos gene promoter. HB‐EGF enhanced the mRNA expression of tissue‐type plasminogen activator (t‐PA) and plasminogen activator inhlbitor‐1 (PAI‐1) mRNA. However, the enhancement of t‐PA and PAI‐1 by HB‐EGF was less than that by EGF. Heparitinase/chlorate, which digests the heparan sulfate proteoglycan of the endothelial cell surface, restored both t‐PA and PAI‐1 mRNA levels in response to HB‐EGF in a manner similar to that by EGF. HB‐EGF at 10 ng/ml developed tube‐like structures in type I collagen gel at similar levels to that of EGF at 10 ng/ml, suggesting that HB‐EGF is also a potent angiogenic factor in the model system for angiogenesis. The tubulogenesis activity of HB‐EGF is discussed in relation to the expression of the t‐PA and PAI‐1 genes.

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          Most cited references52

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          Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor.

          We have previously shown that Madin-Darby canine kidney (MDCK) epithelial cells grown in collagen gels in the presence of fibroblasts or fibroblast-conditioned medium (CM) form branching tubules, instead of the spherical cysts that develop under control conditions. We now report that the fibroblast-derived molecule responsible for epithelial tubulogenesis is hepatocyte growth factor (HGF). First, addition of exogenous HGF to cultures of MDCK cells induces formation of epithelial tubules. Second, the tubulogenic activity of fibroblast CM is completely abrogated by antibodies to HGF. These results demonstrate that HGF, a polypeptide that was identified as a mitogen for cultured hepatocytes, has the properties of a paracrine mediator of epithelial morphogenesis, and suggest that it may play important roles in the formation of parenchymal organs during embryonic development.
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            Epidermal growth factor.

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              Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation.

              Basic fibroblast growth factor (bFGF) binds to heparan sulfate proteoglycans at the cell surface and to receptors with tyrosine kinase activity. Prevention of binding between cell surface heparan sulfate and bFGF (i) substantially reduces binding of fibroblast growth factor to its cell-surface receptors, (ii) blocks the ability of bFGF to support the growth of Swiss 3T3 fibroblasts, and (iii) induces terminal differentiation of MM14 skeletal muscle cells, which is normally repressed by fibroblast growth factor. These results indicate that cell surface heparan sulfate is directly involved in bFGF cell signaling.
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                Author and article information

                Journal
                Jpn J Cancer Res
                Jpn. J. Cancer Res
                10.1111/(ISSN)1349-7006a
                CAS
                Japanese Journal of Cancer Research : Gann
                Blackwell Publishing Ltd (Oxford, UK )
                0910-5050
                1876-4673
                January 1996
                : 87
                : 1 ( doiID: 10.1111/cas.1996.87.issue-1 )
                : 68-77
                Affiliations
                [ 1 ]Department of Biochemistry, Kyushu University School of Medicine, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812
                [ 2 ]Department of Biochemistry, Osaka University Medical School, 2‐2 Yamadaoka, Suita, Osaka 565
                Author notes
                [*] [* ]To whom correspondence and reprint requests should be addressed.
                Article
                CAE68
                10.1111/j.1349-7006.1996.tb00202.x
                5920984
                8609052
                0dd73ffd-819e-4af1-8217-7046a0818be6
                History
                Page count
                References: 55, Pages: 10
                Categories
                Article
                Custom metadata
                2.0
                January 1996
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.6.9 mode:remove_FC converted:04.11.2015

                angiogenesis,human microvascular endothelial cell,hb‐egf,p91,t‐pa

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