The Platelet-derived Growth Factor Receptor-β Phosphorylates and Activates G Protein-coupled Receptor Kinase-2

Wu, Jiao-Hui; Goswami, Robi; Kim, Luke K.; Miller, William E.; Peppel, Karsten; Freedman, Neil J.

doi:10.1074/jbc.m501473200

Cited by 30 publications

(40 citation statements)

References 54 publications

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“…Our in vitro pulldown and kinase assays further confirm that GRK2 is a direct binding partner and substrate of EGFR (Figure 7). These results are in consistent with those of Wu et al (2005), who reported recently that PDGFR␤ can tyrosyl phosphorylate GRK2 directly. However, EGFR and PDGFR may employ distinct mechanisms to phosphorylate GRK2.…”

Section: Discussionsupporting

confidence: 93%

“…Subsequently, Src phosphorylates and activates GRK2 (Fan et al, 2001). PDGFR-mediated GRK2 tyrosyl phosphorylation activates GRK2 and enhances GRK2-mediated seryl phosphorylation of the PDGFR, an event that reduces PDGFR signaling (Wu et al, 2005). In this study, we showed that EGF treatment regulated internalization of both ␦-and -opioid receptors through EGFR-mediated GRK2 phosphorylation and activation.…”

Section: Discussionmentioning

confidence: 54%

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EGF Transregulates Opioid Receptors through EGFR-mediated GRK2 Phosphorylation and Activation

Chen

Long

et al. 2008

MBoC

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G protein-coupled receptor (GPCR) kinases (GRKs) are key regulators of GPCR function. Here we demonstrate that activation of epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase family, stimulates GRK2 activity and transregulates the function of G protein-coupled opioid receptors. Our data showed that EGF treatment promoted DOR internalization induced by DOR agonist and this required the intactness of GRK2-phosphorylation sites in DOR. EGF stimulation induced the association of GRK2 with the activated EGFR and the translocation of GRK2 to the plasma membrane. After EGF treatment, GRK2 was phosphorylated at tyrosyl residues. Mutational analysis indicated that EGFR-mediated phosphorylation occurred at GRK2 N-terminal tyrosyl residues previously shown as c-Src phosphorylation sites. However, c-Src activity was not required for EGFR-mediated phosphorylation of GRK2. In vitro assays indicated that GRK2 was a direct interactor and a substrate of EGFR. EGF treatment remarkably elevated DOR phosphorylation in cells expressing the wild-type GRK2 in an EGFR tyrosine kinase activity-dependent manner, whereas EGF-stimulated DOR phosphorylation was greatly decreased in cells expressing mutant GRK2 lacking EGFR tyrosine kinase sites. We further showed that EGF also stimulated internalization of -opioid receptor, and this effect was inhibited by GRK2 siRNA. These data indicate that EGF transregulates opioid receptors through EGFR-mediated tyrosyl phosphorylation and activation of GRK2 and propose GRK2 as a mediator of cross-talk from RTK to GPCR signaling pathway.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 54%

EGF Transregulates Opioid Receptors through EGFR-mediated GRK2 Phosphorylation and Activation

Chen

Long

et al. 2008

MBoC

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“…We found that SDF-1α and ITAC resulted in significant rVSMC migration across a range of concentrations tested (Fig. 4A), with a response similar to that of other ligands known to induce rVSMC chemotaxis, such as PDGF (28).…”

Section: Cxcr7 Recruitment Of β-Arrestin Is Associated With Phosphoerkmentioning

confidence: 59%

β-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7

Rajagopal

Kim

Ahn

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

522

561

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Ubiquitously expressed seven-transmembrane receptors (7TMRs) classically signal through heterotrimeric G proteins and are commonly referred to as G protein-coupled receptors. It is now recognized that 7TMRs also signal through β-arrestins, which act as versatile adapters controlling receptor signaling, desensitization, and trafficking. Most endogenous receptors appear to signal in a balanced fashion using both β-arrestin and G protein-mediated pathways. Some 7TMRs are thought to be nonsignaling “decoys” because of their inability to activate typical G protein signaling pathways; it has been proposed that these receptors act to scavenge ligands or function as coreceptors. Here we demonstrate that ligand binding to the decoy receptor CXCR7 does not result in activation of signaling pathways typical of G proteins but does activate MAP kinases through β-arrestins in transiently transfected cells. Furthermore, we observe that vascular smooth muscle cells that endogenously express CXCR7 migrate to its ligand interferon-inducible T-cell alpha chemoattractant (ITAC), an effect that is significantly attenuated by treatment with either a CXCR7 antagonist or β-arrestin depletion by siRNA. This example of an endogenous “β-arrestin-biased” 7TMR that signals through β-arrestin in the absence of G protein activation demonstrates that some 7TMRs encoded in the genome have evolved to signal through β-arrestin exclusively and suggests that other receptors that are currently thought to be orphans or decoys may also signal through such nonclassical pathways.

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“…In cell systems in which GRK2 mediates most of the PDGFinduced seryl phosphorylation of the PDGFR␤, persistent PDGFR␤ signaling results in down-regulation of both GRK2 (27) and the PDGFR␤ (7). To determine which widely expressed GRK (GRK2 or GRK5) mediates most of the PDGFR␤ regulation in SMCs, we first tested whether the expression level of either of these GRKs was regulated coordinately with the PDGFR␤.…”

Section: Resultsmentioning

confidence: 99%

“…To compare these PDGFR␤s under conditions of comparable GRK5 levels (Fig. 11D), we used HEK cells (which lack endogenous PDGFR␤s) (27). We used phosphorylation of PDGFR␤ Tyr 1021 and Tyr 740 as read-outs for PDGFR␤ activation.…”

Section: Pdgf-promoted Smc Migration and Proliferation Arementioning

confidence: 99%

Regulation of the Platelet-derived Growth Factor Receptor-β by G Protein-coupled Receptor Kinase-5 in Vascular Smooth Muscle Cells Involves the Phosphatase Shp2

Goswami²,

Cai

et al. 2006

Journal of Biological Chemistry

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Smooth muscle cell (SMC) proliferation and migration are substantially controlled by the platelet-derived growth factor receptor-␤ (PDGFR␤), which can be regulated by the Ser/Thr kinase G protein-coupled receptor kinase-2 (GRK2). In mouse aortic SMCs, however, we found that prolonged PDGFR␤ activation engendered down-regulation of GRK5, but not GRK2; moreover, GRK5 and PDGFR␤ were coordinately up-regulated in SMCs from atherosclerotic arteries. With SMCs from GRK5 knock-out and cognate wild type mice (five of each), we found that physiologic expression of GRK5 increased PDGF-promoted PDGFR␤ seryl phosphorylation by 3-fold and reduced PDGFR␤-promoted phosphoinositide hydrolysis, thymidine incorporation, and overall PDGFR␤ tyrosyl phosphorylation by ϳ35%. Physiologic SMC GRK5 activity also increased PDGFR␤ association with the phosphatase Shp2 (8-fold), enhanced phosphorylation of PDGFR␤ Tyr 1009 (the docking site for Shp2), and reduced phosphorylation of PDGFR␤ Tyr 1021. Consistent with having increased PDGFR␤-associated Shp2 activity, GRK5-expressing SMCs demonstrated greater PDGF-induced Src activation than GRK5-null cells. GRK5-mediated desensitization of PDGFR␤ inositol phosphate signaling was diminished by Shp2 knock-down or impairment of PDGFR␤/Shp2 association. In contrast to GRK5, physiologic GRK2 activity did not alter PDGFR␤/Shp2 association. Finally, purified GRK5 effected agonist-dependent seryl phosphorylation of partially purified PDGFR␤s. We conclude that GRK5 mediates the preponderance of PDGF-promoted seryl phosphorylation of the PDGFR␤ in SMCs, and, through mechanisms involving Shp2, desensitizes PDGFR␤ inositol phosphate signaling and enhances PDGFR␤-triggered Src activation.

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The Platelet-derived Growth Factor Receptor-β Phosphorylates and Activates G Protein-coupled Receptor Kinase-2

Cited by 30 publications

References 54 publications

EGF Transregulates Opioid Receptors through EGFR-mediated GRK2 Phosphorylation and Activation

EGF Transregulates Opioid Receptors through EGFR-mediated GRK2 Phosphorylation and Activation

β-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7

Regulation of the Platelet-derived Growth Factor Receptor-β by G Protein-coupled Receptor Kinase-5 in Vascular Smooth Muscle Cells Involves the Phosphatase Shp2

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