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J. Biol. Chem. 276 (41): 37802-37808

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

The Inhibitory gamma  Subunit of the Type 6 Retinal Cyclic Guanosine Monophosphate Phosphodiesterase Is a Novel Intermediate Regulating p42/p44 Mitogen-activated Protein Kinase Signaling in Human Embryonic Kidney 293 Cells*

Kah Fei Wan, Balwinder S. Sambi, Mhairi Frame, Rothwelle Tate, and Nigel J. PyneDagger

From the Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 ONR, United Kingdom

The inhibitory gamma  subunits of the retinal rod and cone photoreceptor type 6 retinal cyclic guanosine monophosphate phosphodiesterase (PDEgamma ) are expressed in non-retinal tissues. Here, we show that PDEgamma interacts with the G-protein-coupled receptor kinase 2 signaling system to regulate the epidermal growth factor- and thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase in human embryonic kidney 293 cells. This is based upon several lines of evidence. First, the transfection of cells with an antisense rod PDEgamma plasmid construct, which reduced endogenous rod PDEgamma expression, ablated the epidermal growth factor- and thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase. Second, the transfection of cells with recombinant rod or cone PDEgamma and/or G-protein-coupled receptor kinase 2 increased the stimulation of p42/p44 mitogen-activated protein kinase by epidermal growth factor or thrombin. In contrast, a G-protein-coupled receptor kinase 2 phosphorylation-resistant rod PDEgamma mutant failed to increase the epidermal growth factor- or thrombin-dependent stimulation of p42/p44 mitogen-activated protein kinase and, in fact, functioned as a dominant negative. Thrombin also stimulated the association of endogenous rod PDEgamma with dynamin II, which was increased in cells transfected with rod PDEgamma or G-protein-coupled receptor kinase 2. Dynamin II plays a critical role in regulating endocytosis of receptor signal complexes required for activation of p42/p44 mitogen-activated protein kinase. Therefore, PDEgamma may have an important role in promoting endocytosis of receptor signal complexes leading to the activation of p42/p44 mitogen-activated protein kinase. We conclude that PDEgamma is an entirely novel intermediate regulating mitogenic signaling from both receptor tyrosine kinase and G-protein-coupled receptors in human embryonic kidney 293 cells.


* This work was supported by grants from The Wellcome Trust.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF190928 (mouse rod PDEgamma sequence) and AF190929 (cone PDEgamma sequence from lung).

Dagger To whom correspondence should be addressed. Tel.: 44-141-552-4400 (ext. 2659); Fax: 44-141-552-2562; E-mail: n.j.pyne@strath.ac.uk.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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