Abstract
Basic fibroblast growth factor (bFGF), a ligand of receptor protein-tyrosine kinases, promoted the dissociation of G(s) and had antagonistic stimulatory and inhibitory effects on adenylyl cyclase and NADPH oxidase in human fat cell plasma membranes. The bFGF-induced activation of adenylyl cyclase was blocked by COOH-terminal anti-Galpha(s), indicating that it was mediated by Galpha(s). The inhibitory action of bFGF was mimicked by exogenously supplied Gbetagamma-subunits and was reversed by anti-Gbeta(1/2), or betaARK-CT, a COOH-terminal beta-adrenergic receptor kinase fragment that specifically binds free Gbetagamma, indicating that it was transduced by Gbetagamma complexes. The bFGF-induced inhibition of NADPH-dependent H(2)O(2) generation was also reversed by peptide 100-119, an inhibitor of G(s) activation by ligand-occupied beta-adrenergic receptors, indicating that the Gbetagamma complexes mediating the inhibitory action of the growth factor are derived from G(s). The findings suggest a direct, non-kinase-dependent, coupling of bFGF receptor(s) to G(s) and provide the first example of a ligand of receptor protein-tyrosine kinases that is capable of utilizing both types of component subunits of a single heterotrimeric G protein for dual signaling in a single cell type.
Highlights
Gs and provide the first example of a ligand of receptor protein-tyrosine kinases that is capable of utilizing both types of component subunits of a single heterotrimeric
In this report it is shown that Basic fibroblast growth factor (bFGF), a ligand of receptor protein-tyrosine kinases, stimulates adenylyl cyclase and inhibits NADPH-dependent H2O2 generation in human fat cell plasma membranes
The mechanisms by which bFGF elicited its antagonistic stimulatory and inhibitory effects on adenylyl cyclase and NADPH oxidase were confined to the plasma membrane, independent of second messengers, and operated in the absence of ATP, indicating that established pathways of signal transduction, including the tyrosine kinase activity of bFGF receptor(s) were not involved
Summary
Gs and provide the first example of a ligand of receptor protein-tyrosine kinases that is capable of utilizing both types of component subunits of a single heterotrimeric. Mature human adipocytes and 3T3 L1-preadipocytes contain a plasma membrane-bound H2O2 generating system that is under antagonistic control by various hormones, growth factors, and cytokines, including ligands of receptor protein-tyrosine kinases, such as insulin and various isoforms of PDGF and FGF (6, 10 –14). In this work we examined whether the inhibitory effect of bFGF, another ligand of tyrosine kinase receptors, on NADPHdependent H2O2 generation is transmitted by a G protein. The expression of bFGF is decreased appreciably during adipose differentiation and is increased in obesity [4] Another member of the FGF family, aFGF (FGF-1), accelerated the conversion of 3T3 L1-preadipocytes to adipocytes in the presence of insulin and was adipogenic in itself [6]
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