title: Distinct functional domains of TGF-beta bind receptors on endothelial cells.
abstract: Transforming growth factor-beta (TGF-beta) is a multi-functional regulator of cell growth and differentiation. Three distinct isoforms of TGF-beta exist having similar, but not identical actions. TGF-beta 1, but not TGF-beta 2, binds to T beta RII and also to endoglin, a cell surface protein abundant on endothelial cells. In contrast, the affinity constant of TGF-beta 2 for alpha 2-macroglobulin is 10-fold greater than that of TGF-beta 1. TGF-beta 2 also binds better than TGF-beta 1 to a glycosyl phosphatidylinositol (GPI)-linked binding protein expressed on vascular endothelial cells. Using chimeric TGF-beta molecules, in which selected regions of TGF-beta 1 have been exchanged for the corresponding region of TGF-beta 2, we demonstrate here that amino acids 92-95 or 94-98 of TGF-beta determine isoform specific binding to endoglin. In contrast, exchange of only amino acids 95 and 98 did not alter TGF-beta specificity. Isoform specific binding to a GPI-linked protein on EJG endothelial cells was modulated by a region containing amino acids 40-68, although exchange of only amino acids 40-47 did not confer isoform specific binding. Significantly, the 92-98 region also modulates binding of TGF-beta to the type II receptor whereas isoform specific binding to alpha 2-macroglobulin requires concerted exchange of amino acids 45 and 47. Taken together, these results show that at least three different functional domains are important modulators of TGF-beta interaction with binding proteins and receptors.
authors.affiliation: Edge BioSystems, Inc., Gaithersburg, MD 20879, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Qian
authors.forename: N
authors.initials: N
authors.lastname: Dumont
authors.forename: M D
authors.initials: MD
authors.lastname: O'Connor-McCourt
authors.forename: J K
authors.initials: JK
authors.lastname: Burmester
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000511:alpha-Macroglobulins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II