Both homodimeric isoforms of PDGF (AA and BB) have mitogenic and chemotactic activity and stimulate phosphoinositol turnover.
Platelet-derived growth factor (PDGF) occurs as three dimeric isoforms, AA, BB, and AB, which were previously shown to bind to two receptors with different isoform-specificity, the A/B-type (binds all three isoforms) and the B-type (binds only PDGF-BB). Results from competition binding experiments with Swiss 3T3 cells suggest the existence of a third receptor type, which recognizes PDGF-AB and PDGF-BB. Furthermore, Swiss 3T3 cells and human dermal fibroblasts express different relative and absolute levels of these receptor types. In particular, Swiss 3T3 cells express 90,000 PDGF-AA binding sites (A/B-receptors) per cell, whereas human fibroblasts express only 20,000 A/B-receptors per cell. All three PDGF isoforms were tested in either cell type for their effect on DNA synthesis. PDGF-BB and PDGF-AA were also tested in Swiss 3T3 cells for their effect on inositol phospholipid metabolism and chemotaxis. Each isoform promoted all three processes dose-dependently, but there were differences in the maximum cellular responses elicited. These responses reflect the capacity of the cells to bind the individual isoforms. These results demonstrate that the previous distinctions in responsiveness to the different PDGF isoforms are primarily a consequence of the differences in the levels of surface expression of the various isoform-specific receptor types, rather than of the differences in the intrinsic activity of these isoforms. Furthermore, these results suggest that all types of PDGF receptors are capable of responding to their respective ligands by mediating phosphoinositide breakdown, chemotactic responses, and DNA synthesis. Whether they exhibit other functional differences remains to be seen.
Hosang
M
M
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd, Basle, Switzerland.
Rouge
M
M
Wipf
B
B
Eggimann
B
B
Kaufmann
F
F
Hunziker
W
W
D000818:Animals; D001667:Binding, Competitive; D002630:Chemotactic Factors; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D008934:Mitogens; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology* / Q000648:ultrastructure; D011956:Receptors, Cell Surface / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D013403:Sugar Phosphates / Q000378:metabolism*
D002630:Chemotactic Factors; D007295:Inositol Phosphates; D046911:Macromolecular Substances; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D013403:Sugar Phosphates; D004247:DNA; D017479:Receptors, Platelet-Derived Growth Factor