Mechanisms of Fibroblast Growth Factor 2 Intracellular Processing: A Kinetic Analysis of the Role of Heparan Sulfate Proteoglycans†
Identifieur interne : 002455 ( Main/Exploration ); précédent : 002454; suivant : 002456Mechanisms of Fibroblast Growth Factor 2 Intracellular Processing: A Kinetic Analysis of the Role of Heparan Sulfate Proteoglycans†
Auteurs : Gizette V. Sperinde [États-Unis] ; Matthew A. Nugent [États-Unis]Source :
- Biochemistry [ 0006-2960 ] ; 2000.
Abstract
The interaction of fibroblast growth factor 2 (FGF-2) with heparan sulfate proteoglycans (HSPG) has been demonstrated to enhance receptor binding and alter the intracellular distribution of internalized FGF-2. In the present study, the intracellular fate of FGF-2 was analyzed in vascular smooth muscle cells (VSMC) under native and HSPG-deficient conditions. HSPG-deficient cells were generated by treatment with sodium chlorate. Cells were incubated with FGF-2 at 37 °C for prolonged periods (0−48 h) to allow for FGF-2 uptake and processing. Processing of FGF-2 occurred in stages. Initially a family of low molecular weight (LMW) fragments (4−10 kDa) were detected that accumulated to much higher (∼10-fold) levels in native compared to heparan sulfate-deficient cells. Pulse−chase experiments revealed that the half-life of these LMW intermediates was significantly greater in native (∼18 h) compared to HSPG-deficient cells (∼4 h). Rate constants for FGF-2 processing were derived by modeling the uptake and processing of FGF-2 as a set of first-order differential equations. The kinetic analysis indicated that the greatest differences between native and HSPG-deficient VSMC was in the formation of LMW and further suggested that these FGF-2 products appear to represent a stable subpool of internal FGF-2 that is favored in cells that contain HSPG. Thus, HSPG might function as a cellular switch between immediate and prolonged signal activation by heparin-binding growth factors such as FGF-2. In the absence of HSPG, FGF-2 can interact with and activate its receptor, yet in the presence of HSPG, FGF-2 might be able to mediate prolonged or unique biological responses through intracellular processes.
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DOI: 10.1021/bi992243d
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Analysis of the Role of Heparan Sulfate Proteoglycans<ref type="bib" target="#bi992243dAF2"><hi rend="superscript">†</hi></ref></title><author><name sortKey="Sperinde, Gizette V" sort="Sperinde, Gizette V" uniqKey="Sperinde G" first="Gizette V." last="Sperinde">Gizette V. Sperinde</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Departments of Biochemistry and Ophthalmology, Boston University School of Medicine, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Nugent, Matthew A" sort="Nugent, Matthew A" uniqKey="Nugent M" first="Matthew A." last="Nugent">Matthew A. Nugent</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Departments of Biochemistry and Ophthalmology, Boston University School of Medicine, Boston</wicri:cityArea></affiliation><affiliation wicri:level="3"><country wicri:rule="url">États-Unis</country><wicri:regionArea> Correspondence should be addressed to this author at the Department of Biochemistry, Room K225, Boston University School ofMedicine, 716 Albany St., Boston</wicri:regionArea><placeName><settlement type="city">Boston</settlement><region type="state">Massachusetts</region></placeName></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Biochemistry</title><title level="j" type="abbrev">Biochemistry</title><idno type="ISSN">0006-2960</idno><idno type="eISSN">1520-4995</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published" when="2000-03-10">2000</date><date when="2000-04-04">2000</date><biblScope unit="vol">39</biblScope><biblScope unit="issue">13</biblScope><biblScope unit="page" from="3788">3788</biblScope><biblScope unit="page" to="3796">3796</biblScope></imprint><idno type="ISSN">0006-2960</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-2960</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The interaction of fibroblast growth factor 2 (FGF-2) with heparan sulfate proteoglycans (HSPG) has been demonstrated to enhance receptor binding and alter the intracellular distribution of internalized FGF-2. In the present study, the intracellular fate of FGF-2 was analyzed in vascular smooth muscle cells (VSMC) under native and HSPG-deficient conditions. HSPG-deficient cells were generated by treatment with sodium chlorate. Cells were incubated with FGF-2 at 37 °C for prolonged periods (0−48 h) to allow for FGF-2 uptake and processing. Processing of FGF-2 occurred in stages. Initially a family of low molecular weight (LMW) fragments (4−10 kDa) were detected that accumulated to much higher (∼10-fold) levels in native compared to heparan sulfate-deficient cells. Pulse−chase experiments revealed that the half-life of these LMW intermediates was significantly greater in native (∼18 h) compared to HSPG-deficient cells (∼4 h). Rate constants for FGF-2 processing were derived by modeling the uptake and processing of FGF-2 as a set of first-order differential equations. The kinetic analysis indicated that the greatest differences between native and HSPG-deficient VSMC was in the formation of LMW and further suggested that these FGF-2 products appear to represent a stable subpool of internal FGF-2 that is favored in cells that contain HSPG. Thus, HSPG might function as a cellular switch between immediate and prolonged signal activation by heparin-binding growth factors such as FGF-2. In the absence of HSPG, FGF-2 can interact with and activate its receptor, yet in the presence of HSPG, FGF-2 might be able to mediate prolonged or unique biological responses through intracellular processes.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Massachusetts</li></region><settlement><li>Boston</li></settlement></list><tree><country name="États-Unis"><region name="Massachusetts"><name sortKey="Sperinde, Gizette V" sort="Sperinde, Gizette V" uniqKey="Sperinde G" first="Gizette V." last="Sperinde">Gizette V. Sperinde</name></region><name sortKey="Nugent, Matthew A" sort="Nugent, Matthew A" uniqKey="Nugent M" first="Matthew A." last="Nugent">Matthew A. Nugent</name><name sortKey="Nugent, Matthew A" sort="Nugent, Matthew A" uniqKey="Nugent M" first="Matthew A." last="Nugent">Matthew A. Nugent</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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