The inhibitory gamma subunit of the type 6 retinal cGMP phosphodiesterase functions to link c-Src and G-protein-coupled receptor kinase 2 in a signaling unit that regulates p42/p44 mitogen-activated protein kinase by epidermal growth factor.
The inhibitory gamma subunit of the retinal photoreceptor type 6 cGMP phosphodiesterase (PDEgamma) is phosphorylated by G-protein-coupled receptor kinase 2 on threonine 62 and regulates the epidermal growth factor- dependent stimulation of p42/p44 mitogen-activated protein kinase in human embryonic kidney 293 cells. We report here that PDEgamma is in a ... pre-formed complex with c-Src and that stimulation of cells with epidermal growth factor promotes the association of GRK2 with this complex. c-Src has a critical role in the stimulation of the p42/p44 mitogen-activated protein kinase cascade by epidermal growth factor, because c-Src inhibitors block the activation of this kinase by the growth factor. Mutation of Thr-62 (to Ala) in PDEgamma produced a GRK2 phosphorylation-resistant mutant that was less effective in associating with GRK2 in response to epidermal growth factor and did not potentiate the stimulation of p42/p44 mitogen-activated protein kinase by this growth factor. The transcript for a short splice variant version of PDEgamma lacking the Thr-62 phosphorylation site is also expressed in certain mammalian cells and, in common with the Thr-62 mutant, failed to potentiate the stimulatory effect of epidermal growth factor on p42/p44 mitogen-activated protein kinase. The mutation of Thr-22 (to Ala) in PDEgamma, which is a site for phosphorylation by p42/p44 mitogen-activated protein kinase, resulted in a prolonged activation of p42/p44 mitogen-activated protein kinase by epidermal growth factor, suggesting a role for this phosphorylation event in the negative feedback control of PDEgamma.
Mesh Terms:
3',5'-Cyclic-GMP Phosphodiesterases, Adaptor Proteins, Signal Transducing, Alternative Splicing, Binding Sites, Cell Line, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 6, Epidermal Growth Factor, GRB2 Adaptor Protein, Humans, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Muscle, Smooth, Mutagenesis, Site-Directed, Mutation, Phosphorylation, Precipitin Tests, Protein Binding, Proteins, Recombinant Proteins, Signal Transduction, Thrombin, Transfection, beta-Adrenergic Receptor Kinases, src-Family Kinases
3',5'-Cyclic-GMP Phosphodiesterases, Adaptor Proteins, Signal Transducing, Alternative Splicing, Binding Sites, Cell Line, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 6, Epidermal Growth Factor, GRB2 Adaptor Protein, Humans, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Muscle, Smooth, Mutagenesis, Site-Directed, Mutation, Phosphorylation, Precipitin Tests, Protein Binding, Proteins, Recombinant Proteins, Signal Transduction, Thrombin, Transfection, beta-Adrenergic Receptor Kinases, src-Family Kinases
J. Biol. Chem.
Date: May. 16, 2003
PubMed ID: 12624098
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