Transactivation of the EGF Receptor: Is the PDGF Receptor an Unexpected Accomplice?

Graves, Lee M.; Han, J.; Earp, H. Shelton

doi:10.1124/mi.2.4.208

Cited by 12 publications

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“…Our study supports these interesting findings and extends them by showing that this can also occur with activating autoantibodies. How the PDGFR affects the EGFR in the absence of its kinase activity is still unknown but could involve the tyrosine kinase c-Src [14]. In experimental models of SSc, the selective Src kinase inhibitor SU6656 reduced the development of dermal fibrosis [48].…”

Section: Discussionmentioning

confidence: 99%

“…In a molecular context, a certain proportion of these receptors are expressed as heterodimers in VSMCs and interestingly, the activation of early signaling events by PDGF in these cells occurs through transactivation of the EGFR via a process that is independent of PDGFR kinase activity but dependent on EGFR kinase activity [13], [14]. Thus, we investigated whether the EGFR might play a role in VSMC stimulation by SSc IgG.…”

Section: Introductionmentioning

confidence: 99%

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Systemic Sclerosis Immunoglobulin Induces Growth and a Pro-Fibrotic State in Vascular Smooth Muscle Cells through the Epidermal Growth Factor Receptor

et al. 2014

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ObjectiveIt has been suggested that autoantibodies in systemic sclerosis (SSc) may induce the differentiation of cultured fibroblasts into myofibroblasts through platelet-derived growth factor receptor (PDGFR) activation. The present study aims to characterize the effects of SSc IgG on vascular smooth muscle cells (VSMCs) and to determine if stimulatory autoantibodies directed to the PDGFR can be detected, and whether they induce a profibrotic response in primary cultured VSMCs.MethodsCultured VSMCs were exposed to IgG fractions purified from SSc-patient or control sera. VSMC responses were then analyzed for ERK1/2 and Akt phosphorylation, PDGFR immunoprecipitation, cellular proliferation, protein synthesis, and pro-fibrotic changes in mRNA expression.ResultsStimulatory activity in IgG fractions was more prevalent and intense in the SSc samples. SSc IgG immunoprecipitated the PDGFR with greater avidity than control IgG. Interestingly, activation of downstream signaling events (e.g. Akt, ERK1/2) was independent of PDGFR activity, but required functional EGFR. We also detected increased protein synthesis in response to SSc IgG (p<0.001) and pro-fibrotic changes in gene expression (Tgfb1 +200%; Tgfb2 −23%; p<0.001)) in VSMCs treated with SSc IgG.ConclusionWhen compared to control IgG, SSc IgG have a higher stimulation index in VSMCs. Although SSc IgG interact with the PDGFR, the observed remodeling signaling events occur through the EGFR in VSMC. Our data thus favour a model of transactivation of the EGFR by SSc-derived PDGFR autoantibodies and suggest the use of EGFR inhibitors in future target identification studies in the field of SSc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systemic Sclerosis Immunoglobulin Induces Growth and a Pro-Fibrotic State in Vascular Smooth Muscle Cells through the Epidermal Growth Factor Receptor

et al. 2014

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“…According to these findings and to previously published data, 27,28 we then hypothesized that a mechanism able to explain at least in part the PDGF-BB-mediated impairment of FGF-2 activity may involve the formation of a heterocomplex containing FGF-R1 and PDGF-R␣. Direct interaction of these molecules was measured in vitro by SPA experiments.…”

Section: Fgf-r1/pdgf-r␣ Direct Interactionmentioning

confidence: 90%

“…All these findings highlight the inhibitory role of PDGF-R␣ as opposed to PDGF-R␤, further indicating their distinct functions despite the overlapping signaling pathways. 36 Previous evidence reports the heterodimerization of the PDGF receptor and epidermal growth factor (EGF) receptor, 27,28 showing that cross-talk of different factors may be mediated, at least in some cases, by heterodimerization of their receptors. FGF-R1 and PDGF-R␣ are both tyrosine kinase receptors and type 1 membrane proteins; the former belongs to the FGF receptor family and has 3 immunoglobulinlike C2-type domains, whereas the latter belongs to the CSF-1/PDGF receptor subfamily and has 5 immunoglobulinlike C2-type domains.…”

Section: Fret Confocal Analysismentioning

confidence: 99%

Heterodimerization of FGF-receptor 1 and PDGF-receptor-α: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells

Faraone

Aguzzi

Ragone

et al. 2006

Blood

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Previous evidence has shown that platelet-derived growth factor-BB (PDGF-BB) and fibroblast growth factor-2 (FGF-2) directly interact with high affinity, leading to potent reciprocal inhibitory effects on bovine endothelial cells and rat vascular smooth muscle cells. In this study, we report that PDGF-BB inhibits a series of FGF-2-induced events, such as proliferation of human umbilical vein endothelial cells (

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“…In pulmonary hypertension, a role of PDGFR-β and EGFR in the improvement of hemodynamic function has been suggested in animal models [29-31]. It is noteworthy in this context that PDGFR-β plays a role in activation of EGFR [32]. In IPAH patients, increased and activated PDGFR-β has been demonstrated in pulmonary arteries [33].…”

Section: Introductionmentioning

confidence: 99%

Platelet-derived growth factor receptor-β and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study

et al. 2011

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IntroductionSystemic sclerosis (SSc) complicated by pulmonary arterial hypertension (PAH) carries a poor prognosis, despite pulmonary vascular dilating therapy. Platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR) are potential therapeutic targets for PAH because of their proliferative effects on vessel remodelling. To explore their role in SScPAH, we compared PDGFR- and EGFR-mmunoreactivity in lung tissue specimens from SScPAH. We compared staining patterns with idiopathic PAH (IPAH) and pulmonary veno-occlusive disease (PVOD), as SScPAH vasculopathy differs from IPAH and sometimes displays features of PVOD. Immunoreactivity patterns of phosphorylated PDGFR-β (pPDGFR-β) and the ligand PDGF-B were evaluated to provide more insight into the patterns of PDGFR-b activation.MethodsLung tissue specimens from five SScPAH, nine IPAH, six PVOD patients and five controls were examined. Immunoreactivity was scored for presence, distribution and intensity.ResultsAll SScPAH and three of nine IPAH cases (P = 0.03) showed PDGFR-β-immunoreactivity in small vessels (arterioles/venules); of five SScPAH vs. two of nine IPAH cases (P = 0.02) showed venous immunoreactivity. In small vessels, intensity was stronger in SScPAH vs. IPAH. No differences were found between SScPAH and PVOD. One of five normal controls demonstrated focally mild immunoreactivity. There were no differences in PDGF-ligand and pPDGFR-b-immunoreactivity between patient groups; however, pPDGFR-b-immunoreactivity tended to be more prevalent in SScPAH small vasculature compared to IPAH. Vascular EGFR-immunoreactivity was limited to arterial and arteriolar walls, without differences between groups. No immunoreactivity was observed in vasculature of normals.ConclusionsPDGFR-β-immunoreactivity in SScPAH is more common and intense in small- and post-capillary vessels than in IPAH and does not differ from PVOD, fitting in with histomorphological distribution of vasculopathy. PDGFR-β immunoreactivity pattern is not paralleled by pPDGFR-β or PDGF-B patterns. PDGFR-β- and EGFR-immunoreactivity of pulmonary vessels distinguishes PAH patients from controls.

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Transactivation of the EGF Receptor: Is the PDGF Receptor an Unexpected Accomplice?

Cited by 12 publications

References 0 publications

Systemic Sclerosis Immunoglobulin Induces Growth and a Pro-Fibrotic State in Vascular Smooth Muscle Cells through the Epidermal Growth Factor Receptor

Systemic Sclerosis Immunoglobulin Induces Growth and a Pro-Fibrotic State in Vascular Smooth Muscle Cells through the Epidermal Growth Factor Receptor

Heterodimerization of FGF-receptor 1 and PDGF-receptor-α: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells

Platelet-derived growth factor receptor-β and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study

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