Involvement of the platelet‐derived growth factor receptor in angiotensin II‐induced activation of extracellular regulated kinases 1 and 2 in human mesangial cells

Mondorf, Ulrich F.; Geiger, Helmut; Herrero, Martina; Zeuzem, Stefan; Piiper, Albrecht

doi:10.1016/s0014-5793(00)01433-2

Cited by 42 publications

(23 citation statements)

References 37 publications

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“…The phosphorylation levels of PDGFR␣ in relation to its expression levels were increased by 60% Ϯ 9% (mean Ϯ standard error of the mean [SEM]; n ϭ6) over control values (P ϭ 0.01). Since previous studies have shown that such an increase in the phosphorylation levels of PDGFR can elicit mitogenic responses in different cell types (32,42), our results identify PDGFR␣ as a novel player in G␣ 12 -mediated mitogenic signaling. In this context, it is of interest to analyze whether G␣ 12 also stimulates the expression and activation of closely related PDGFR␤.…”

Section: Vol 26 2006 G␣ 12 Transactivation Of Pdgfr␣ 53supporting

confidence: 53%

Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα₁₂

Kumar

Radhakrishnan

et al. 2006

Molecular and Cellular Biology

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Heterotrimeric G proteins regulate diverse cellular responses by coupling heptahelical receptors to intracellular effectors (11,25,35). Of the different ␣-subunits that have been analyzed thus far, the ␣-subunit of the heterotrimeric G protein G12 (G␣ 12 ) shows the most potent mitogenic and oncogenic activities (5, 35). The initial identification of G␣ 12 as the transforming oncogene in Ewing's sarcoma cell lines indicated the critical role of G␣ 12 in oncogenic signaling (5). Consistent with these observations, serum stimulation or mutational activation of G␣ 12 has been shown to stimulate mitogenic pathways in different cell types in addition to inducing neoplastic transformation of 35). NIH 3T3 cells transformed by the GTPase-deficient activated mutant of G␣ 12 (G␣ 12 Q229L, or G␣ 12 QL) show the characteristic oncogenic phenotype defined by the increased proliferation, anchorage-independent growth, reduced growth factor dependency, attenuation of apoptotic signals, and neoplastic cytoskeletal changes (35). Previously, we have shown that the neoplastic growth of NIH 3T3 cells mediated by the activated mutant G␣ 12 involves the expression several unique genes, including platelet-derived growth factor receptor ␣ (PDGFR␣) (25). This finding is of critical interest since the signaling pathways involving PDGFR have been strongly correlated with cell proliferation and neoplastic transformation (18), thus pointing to a possible role of PDGFR␣ in G␣ 12 QL-mediated oncogenic signaling pathways.The receptor kinases PDGFR␣ and PDGFR␤ are activated by dimers of PDGF isoforms, PDGF-A, PDGF-B, PDGF-C, and PDGF-D (18). Distinct homo-or heterodimers of PDGFs activate specific homo-or heterodimers of PDGFR␣ and PDGFR␤ in a tissue-specific and context-specific manner (18). The activation of PDGFRs, leading to their dimerization and transphosphorylation at specific tyrosine residues, provides docking sites for different effector molecules such as Shp, phospholipase C-gamma, and phosphatidylinositol 3-kinase (PI3K) (18). Overexpression of PDGFR␣ or PDGFR␤ and the associated autocrine signaling pathways appear to play an etiological role in tumorigenesis and tumorangiogenesis of different neoplasms including basal cell carcinoma (45), gastrointestinal stromal tumors (17), and ovarian cancers (19,30). It has also been observed that PDGFR, specifically PDGFR␤, is transactivated by G protein-coupled receptors (GPCRs) stimulated by lysophosphatidic acid (LPA) (20), sphingosine-1 phosphate (2), serotonin (33), and angiotensin II (39). However, the underlying signaling mechanisms and the role of the specific G proteins in mediating such transactivation are not fully understood.In the present study, we demonstrate that G␣ 12 QL stimulates the expression and transactivation of PDGFR␣ in NIH 3T3 cells. The ability of transiently expressed G␣ 12 QL to stimulate the expression of PDGFR␣ in 1321N1 astrocytoma cells indicates that such a nexus between G␣ 12 and PDGFR␣ is not restricted to one specific cell type. Our results indicate that...

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Section: Vol 26 2006 G␣ 12 Transactivation Of Pdgfr␣ 53supporting

confidence: 53%

Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα₁₂

Kumar

Radhakrishnan

et al. 2006

Molecular and Cellular Biology

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“…19 Similarly, in mesangial cells, angiotensin activates ERK1/2 through a ligand-independent activation of the PDGF-R, not of the EGF receptor. 35 Our data showing that Ang II is able to phosphorylate PDGF-␤-R support the concept of Ang II-mediated transactivation. 17 Furthermore, our finding that this phosphorylation was inhibited both by AF385, the PDGF-␤-R antibody, and by RPR101511A, the PDGF-R tyrosine kinase inhibitor, supports the effectiveness of these 2 modes of PDGF-R inhibition.…”

Section: Role Of the Renin-angiotensin System In Pressure-mediated Ersupporting

confidence: 75%

Pressure-Induced Activation of Extracellular Signal-Regulated Kinase 1/2 in Small Arteries

Eskildsen‐Helmond

Mulvany

2003

Hypertension

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Abstract-Extracellular signal-regulated kinase 1/2 (ERK1/2) may play a central signaling role in vascular remodeling. We investigated a possible combined role for the renin-angiotensin system and platelet-derived growth factor ␤-receptor (PDGF-␤-R) in pressure-induced ERK1/2 activation in intact rat mesenteric small arteries. In an organ culture model, vessels were pressurized (70 mm Hg) for 1 hour plus a 5-minute intervention period. The intervention was either a rise in intraluminal pressure (up to 140 mm Hg) or challenge with angiotensin II (Ang II, 0.1 mol/L) or PDGF-BB (30 g/L). ERK1/2 activation was determined by Western blotting as formation of phosphorylated ERK1/2. All interventions caused ERK1/2 activation that was inhibited by the MEK inhibitor PD98059. The response to pressure was inhibited by an ACE inhibitor (perindoprilat), an Ang II receptor type 1 (R-AT 1 ) antagonist (candesartan), and tyrosine kinase inhibitors (genistein, herbimycin A). An R-AT 2 antagonist (PD123319) had no significant effect. Both a PDGF-receptor tyrosine kinase inhibitor (RPR101511A) and a neutralizing PDGF-␤-R antibody (AF385) inhibited the activation of ERK1/2 caused by PDGF-BB, Ang II, and pressure. That the latter interventions could indeed inhibit the PDGF-␤-R was supported by experiments with unmounted vessels in which PDGF-␤-R activation was measured by Western blot; both PDGF-BB and Ang II-mediated PDGF-␤-R activation were inhibited by RPR101511A and AF385. Immunohistochemistry showed that ERK1/2 and PDGF-␤-R was located in the adventitia, tunica media, and intima. The results suggest that pressure in rat mesenteric small arteries causes acute activation of ERK1/2 through pathways involving Ang II and PDGF-␤-R.

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“…Upon acute AngII infusion, activation of PDGFR occurs in the vasculature of mice and rats. ACE-inhibitor infusion reduced aortic PDGFR phosphorylation and ERK activity , implicating PDGFR as downstream modulator of hypertensive vascular remodeling in vivo (Linseman et al, 1995;Heeneman et al, 2000;Mondorf et al, 2000;Gao et al, 2006). AngII infusion also leads to activation of epidermal growth factor receptor (Zhang et al, 2009) in the vasculature .…”

Section: E Signalingmentioning

confidence: 92%

“…Transactivation of Receptor Tyrosine Kinase Signaling. AT 1 receptor-induced transactivation of platelet derived growth factor receptor (PDGFR) modulates cell growth and migration (Heeneman et al, 2000;Suzuki and Eguchi, 2006) in VSMCs and mesangial cells (Linseman et al, 1995;Mondorf et al, 2000). This response is blocked by losartan and other ARBs.…”

Section: E Signalingmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

Karnik

Ünal

Kemp

et al. 2015

Pharmacological Reviews

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300

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Involvement of the platelet‐derived growth factor receptor in angiotensin II‐induced activation of extracellular regulated kinases 1 and 2 in human mesangial cells

Cited by 42 publications

References 37 publications

Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα₁₂

Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα₁₂

Pressure-Induced Activation of Extracellular Signal-Regulated Kinase 1/2 in Small Arteries

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

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Involvement of the platelet‐derived growth factor receptor in angiotensin II‐induced activation of extracellular regulated kinases 1 and 2 in human mesangial cells

Cited by 42 publications

References 37 publications

Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα12

Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα12

Pressure-Induced Activation of Extracellular Signal-Regulated Kinase 1/2 in Small Arteries

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

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Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα₁₂

Transactivation of Platelet-Derived Growth Factor Receptor α by the GTPase-Deficient Activated Mutant of Gα₁₂