Heparan sulfate proteoglycans as transducers of FGF-2 signalling.

The fibroblast growth factor-2 (FGF-2) low-affinity binding sites, heparan sulfate proteoglycans (HSPGs), function as modulators of FGF-2 activity. It is noteworthy that HSPG binding protects FGF-2 from denaturation and proteolytic degradation, provides a matrix-bound or cell-surface reservoir of this factor for the cells and is required for the activation of FGF high-affinity receptors. In our study we investigated the biological meaning of FGF-2 internalization mediated through its low-affinity binding sites, HSPGs. Using as model system L6 myoblasts lacking endogenous FGF receptors (FGFRs), we demonstrated that these cells internalize FGF-2 efficiently through an HSPG-mediated pathway. FGF-2 internalization occurring through HSPGs was paralleled by an increase in the activity of urokinase plasminogen activator (u-PA). The u-PA-inducing activity of FGF-2 was strictly correlated to its internalization, as chlorate treatment, which causes a strong inhibition of FGF-2 internalization, abrogated the u-PA-inducing activity of FGF-2. In addition, expression of functional FGF high-affinity receptors (FGFR-1) did not enhance u-PA in L6 myoblasts upon FGF-2 stimulation. According to our results we propose that FGF-2 internalization mediated through HSPGs may transduce FGF-2 signalling such as u-PA-activity stimulation. Thus, HSPGs may act as direct transducers of FGF signalling and indeed, different FGF-signalling pathways must exist.

[1]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[2]  N. Quarto,et al.  Fibroblast growth factor-2 (FGF-2) in the nucleus: translocation process and targets. , 1994, Biochemical pharmacology.

[3]  T. Kurokawa,et al.  Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property , 1993, Molecular and cellular biology.

[4]  F. Blasi.  Urokinase and urokinase receptor: A paracrine/autocrine system regulating cell migration and invasiveness , 1993, BioEssays : news and reviews in molecular, cellular and developmental biology.

[5]  M. Rusnati,et al.  Internalization of basic fibroblast growth factor (bFGF) in cultured endothelial cells: Role of the low affinity heparin‐like bFGF receptors , 1993, Journal of cellular physiology.

[6]  R. Forough,et al.  Heat shock induces the release of fibroblast growth factor 1 from NIH 3T3 cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Moscatelli,et al.  Basic fibroblast growth factor is internalized through both receptor-mediated and heparan sulfate-mediated mechanisms. , 1992, The Journal of biological chemistry.

[8]  K. Matsumoto,et al.  Cloning and characterization of an androgen-induced growth factor essential for the androgen-dependent growth of mouse mammary carcinoma cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[9]  E. Edelman,et al.  Kinetics of basic fibroblast growth factor binding to its receptor and heparan sulfate proteoglycan: a mechanism for cooperactivity. , 1992, Biochemistry.

[10]  Nanxin Li,et al.  Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis , 1992, Nature.

[11]  J. Escobedo,et al.  Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Ca2+ flux but not mitogenesis , 1992, Nature.

[12]  M. Jaye,et al.  Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. , 1992, Biochimica et biophysica acta.

[13]  F. Blasi,et al.  Modulation of activities and RNA level of the components of the plasminogen activation system during fusion of human myogenic satellite cells in vitro. , 1992, Developmental biology.

[14]  H. Hanafusa,et al.  Characterization of the murine BEK fibroblast growth factor (FGF) receptor: activation by three members of the FGF family and requirement for heparin. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J G Flanagan,et al.  Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells , 1992, Molecular and cellular biology.

[16]  S. Werner,et al.  Differential splicing in the extracellular region of fibroblast growth factor receptor 1 generates receptor variants with different ligand-binding specificities , 1992, Molecular and cellular biology.

[17]  D. Rifkin,et al.  Basic fibroblast growth factor released by single, isolated cells stimulates their migration in an autocrine manner. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[18]  H. Prats,et al.  Nuclear Translocation of Basic Fibroblast Growth Factor a , 1991, Annals of the New York Academy of Sciences.

[19]  A. Bensadoun,et al.  Effect of chlorate on the sulfation of lipoprotein lipase and heparan sulfate proteoglycans. Sulfation of heparan sulfate proteoglycans affects lipoprotein lipase degradation. , 1991, The Journal of biological chemistry.

[20]  D. Rifkin,et al.  Selective expression of high molecular weight basic fibroblast growth factor confers a unique phenotype to NIH 3T3 cells. , 1991, Cell regulation.

[21]  L. Williams,et al.  The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain , 1991, Molecular and cellular biology.

[22]  P. Spear,et al.  Fibroblast growth factor receptor: does it have a role in the binding of herpes simplex virus? , 1991, Science.

[23]  B. Olwin,et al.  Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation , 1991, Science.

[24]  W. Heath,et al.  Mutations in the heparin-binding domains of human basic fibroblast growth factor alter its biological activity. , 1991, Biochemistry.

[25]  M. Klagsbrun,et al.  The fibroblast growth factor family. , 1991, Cancer cells.

[26]  D. Rifkin,et al.  The NH2‐terminal extension of high molecular weight bFGF is a nuclear targeting signal , 1991, Journal of cellular physiology.

[27]  A. Isacchi,et al.  A six-amino acid deletion in basic fibroblast growth factor dissociates its mitogenic activity from its plasminogen activator-inducing capacity. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Jaye,et al.  The mRNAs encoding acidic FGF, basic FGF and FGF receptor are coordinately downregulated during myogenic differentiation. , 1991, Development.

[29]  Jeffrey D. Esko,et al.  Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor , 1991, Cell.

[30]  M. Klagsbrun,et al.  Extracellular matrix‐resident basic fibroblast growth factor: Implication for the control of angiogenesis , 1991, Journal of cellular biochemistry.

[31]  M. Jaye,et al.  Possible dissociation of the heparin-binding and mitogenic activities of heparin-binding (acidic fibroblast) growth factor-1 from its receptor-binding activities by site-directed mutagenesis of a single lysine residue , 1990, The Journal of cell biology.

[32]  Y. Courtois,et al.  Related fibroblast growth factor receptor genes exist in the human genome. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[33]  D. Rifkin,et al.  Heparin and heparan sulfate increase the radius of diffusion and action of basic fibroblast growth factor , 1990, The Journal of cell biology.

[34]  P. Barr,et al.  Ligand-affinity cloning and structure of a cell surface heparan sulfate proteoglycan that binds basic fibroblast growth factor. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Klein,et al.  Metabolism of endothelial cell-bound lipoprotein lipase. Evidence for heparan sulfate proteoglycan-mediated internalization and recycling. , 1990, The Journal of biological chemistry.

[36]  D. Rifkin,et al.  Nuclear and cytoplasmic localization of different basic fibroblast growth factor species , 1990, Journal of cellular physiology.

[37]  D. Moscatelli,et al.  A murine fibroblast growth factor (FGF) receptor expressed in CHO cells is activated by basic FGF and Kaposi FGF. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[38]  G. Barlovatz-Meimon,et al.  Slow and fast rat skeletal muscles differ in their plasminogen activator activities. , 1990, European journal of cell biology.

[39]  B. Olwin,et al.  Fibroblast growth factor receptor levels decrease during chick embryogenesis , 1990, The Journal of cell biology.

[40]  N. Quarto,et al.  Transformation of NIH 3T3 cells with basic fibroblast growth factor or the hst/K-fgf oncogene causes downregulation of the fibroblast growth factor receptor: reversal of morphological transformation and restoration of receptor number by suramin , 1989, The Journal of cell biology.

[41]  D. Rifkin,et al.  Recent developments in the cell biology of basic fibroblast growth factor , 1989, The Journal of cell biology.

[42]  D. Rifkin,et al.  Role of extracellular matrix in the action of basic fibroblast growth factor: Matrix as a source of growth factor for long‐term stimulation of plasminogen activator production and DNA synthesis , 1989, Journal of cellular physiology.

[43]  S. Singer,et al.  Identification of a developmentally regulated protein-tyrosine kinase by using anti-phosphotyrosine antibodies to screen a cDNA expression library. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[44]  A. Sommer,et al.  Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[45]  B. Olwin,et al.  Cell type and tissue distribution of the fibroblast growth factor receptor , 1989, Journal of cellular biochemistry.

[46]  M. Jalkanen,et al.  Molecular cloning of syndecan, an integral membrane proteoglycan , 1989, The Journal of cell biology.

[47]  J. Lélias,et al.  High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG codons. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[48]  J. Folkman,et al.  Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules. , 1989, Biochemistry.

[49]  D. Rifkin,et al.  Interaction of heparin with human basic fibroblast growth factor: Protection of the angiogenic protein from proteolytic degradation by a glycosaminoglycan , 1989, Journal of cellular physiology.

[50]  D. Rifkin,et al.  Autocrine activities of basic fibroblast growth factor: regulation of endothelial cell movement, plasminogen activator synthesis, and DNA synthesis , 1988, The Journal of cell biology.

[51]  D. Rifkin,et al.  Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation , 1988, The Journal of cell biology.

[52]  D. Ingber,et al.  A heparin-binding angiogenic protein--basic fibroblast growth factor--is stored within basement membrane. , 1988, The American journal of pathology.

[53]  T. Kurokawa,et al.  Transformation of mouse BALB/c 3T3 cells with human basic fibroblast growth factor cDNA , 1988, Molecular and cellular biology.

[54]  P. Barr,et al.  Acidic and basic fibroblast growth factors stimulate tyrosine kinase activity in vivo. , 1988, The Journal of biological chemistry.

[55]  J. Teissié,et al.  Basic fibroblast growth factor enters the nucleolus and stimulates the transcription of ribosomal genes in ABAE cells undergoing G0----G1 transition. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[56]  C. Clegg,et al.  Growth factor control of skeletal muscle differentiation: commitment to terminal differentiation occurs in G1 phase and is repressed by fibroblast growth factor , 1987, The Journal of cell biology.

[57]  D. Belin,et al.  Amiloride selectively inhibits the urokinase‐type plasminogen activator , 1987, FEBS letters.

[58]  D. Moscatelli,et al.  High and low affinity binding sites for basic fibroblast growth factor on cultured cells: Absence of a role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells , 1987, Journal of cellular physiology.

[59]  J. Folkman,et al.  Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[60]  D. Rifkin,et al.  Identification of a pituitary factor responsible for enhancement of plasminogen activator activity in breast tumor cells. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[61]  J. Fiddes,et al.  Human basic fibroblast growth factor: nucleotide sequence and genomic organization. , 1986, The EMBO journal.

[62]  D. Gospodarowicz,et al.  Heparin protects basic and acidic FGF from inactivation , 1986, Journal of cellular physiology.

[63]  J. Fiddes,et al.  Nucleotide sequence of a bovine clone encoding the angiogenic protein, basic fibroblast growth factor. , 1986, Science.

[64]  S. O’Brien,et al.  Human endothelial cell growth factor: cloning, nucleotide sequence, and chromosome localization. , 1986, Science.

[65]  S. S. Huang,et al.  Association of bovine brain-derived growth factor receptor with protein tyrosine kinase activity. , 1986, The Journal of biological chemistry.

[66]  B. Olwin,et al.  Identification of the fibroblast growth factor receptor of Swiss 3T3 cells and mouse skeletal muscle myoblasts. , 1986, Biochemistry.

[67]  J. V. Van Wyk,et al.  Biphasic concentration dependency of stimulation of myoblast differentiation by somatomedins. , 1986, The American journal of physiology.

[68]  N. Fedarko,et al.  Transport of heparan sulfate into the nuclei of hepatocytes. , 1986, The Journal of biological chemistry.

[69]  M. Presta,et al.  Purification of a factor from human placenta that stimulates capillary endothelial cell protease production, DNA synthesis, and migration. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[70]  D. Gospodarowicz,et al.  The identification and partial characterization of the fibroblast growth factor receptor of baby hamster kidney cells. , 1985, The Journal of biological chemistry.

[71]  M. Jalkanen,et al.  The cell surface proteoglycan from mouse mammary epithelial cells bears chondroitin sulfate and heparan sulfate glycosaminoglycans. , 1985, The Journal of biological chemistry.

[72]  R. Duvoisin,et al.  Cloning, nucleotide sequencing and expression of cDNAs encoding mouse urokinase-type plasminogen activator. , 1985, European journal of biochemistry.

[73]  E. Neufeld,et al.  Phosphoinositide interconversion in thrombin-stimulated human platelets. , 1985, The Journal of biological chemistry.

[74]  A. Granelli‐Piperno,et al.  A study of proteases and protease-inhibitor complexes in biological fluids , 1978, The Journal of experimental medicine.

[75]  Olli Saksela.  Release of Basic Fibroblast Growth Factor-Heparan Sulfate Complexes from Endothelial Cells by Plasminogen Activator-mediated Proteolytic Activity , 2002 .

[76]  T. Fleming,et al.  Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[77]  D. Rifkin,et al.  Transformation by basic fibroblast growth factor requires high levels of expression: comparison with transformation by hst/K-fgf. , 1989, Oncogene research.