Protein Tyrosine Phosphatase SHP-2 Is Positively Involved in Platelet-Derived Growth Factor–Signaling in Vascular Neointima Formation via the Reactive Oxygen Species–Related Pathway

Won, Kyung‐Jong; Lee, Hwan Myung; Lee, Chang-Kwon; Hai, Lin; Na, Haerang; Lim, Ki Won; Roh, Hui Yul; Sim, Seobo; Song, Hyuk; Choi, Wahn Soo; Lee, Seung Hyun; Kim, Bokyung

doi:10.1254/jphs.10250fp

Cited by 20 publications

(11 citation statements)

References 36 publications

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“…Previous studies have shown that PDGF activation enhanced SHP-2 and PTP1B activity (46,47), which may explain our results. We have reported that activation of PKCδ induces the expression of SHP-1 in cultured pericytes exposed to high glucose concentrations and inhibits the PDGF signaling pathway contributing to pericyte apoptosis (23).…”

Section: Discussionsupporting

confidence: 75%

PKCδ Impaired Vessel Formation and Angiogenic Factor Expression in Diabetic Ischemic Limbs

et al. 2013

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Decreased collateral vessel formation in diabetic peripheral limbs is characterized by abnormalities of the angiogenic response to ischemia. Hyperglycemia is known to activate protein kinase C (PKC), affecting the expression and activity of growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The current study investigates the role of PKCδ in diabetes-induced poor collateral vessel formation and inhibition of angiogenic factors expression and actions. Ischemic adductor muscles of diabetic Prkcd+/+ mice exhibited reduced blood reperfusion, vascular density, and number of small vessels compared with nondiabetic Prkcd+/+ mice. By contrast, diabetic Prkcd−/− mice showed significant increased blood flow, capillary density, and number of capillaries. Although expression of various PKC isoforms was unchanged, activation of PKCδ was increased in diabetic Prkcd+/+ mice. VEGF and PDGF mRNA and protein expression were decreased in the muscles of diabetic Prkcd+/+ mice and were normalized in diabetic Prkcd−/− mice. Furthermore, phosphorylation of VEGF receptor 2 (VEGFR2) and PDGF receptor-β (PDGFR-β) were blunted in diabetic Prkcd+/+ mice but elevated in diabetic Prkcd−/− mice. The inhibition of VEGFR2 and PDGFR-β activity was associated with increased SHP-1 expression. In conclusion, our data have uncovered the mechanisms by which PKCδ activation induced poor collateral vessel formation, offering potential novel targets to regulate angiogenesis therapeutically in diabetic patients.

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Section: Discussionsupporting

confidence: 75%

PKCδ Impaired Vessel Formation and Angiogenic Factor Expression in Diabetic Ischemic Limbs

et al. 2013

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“…SHP-2 is abundant in vascular SMC [41], and its expression levels are elevated upon vascular injury [42], [43]. PDGF-mediated smooth muscle cell migration is inhibited by the SHP-2 inhibitor NSC-87877 and interestingly, oral administration of the SHP-2 inhibitor, NSC-87877 significantly suppressed neointima formation in a rat model of carotid artery injury [44].…”

Section: Discussionmentioning

confidence: 99%

The LDL Receptor-Related Protein 1 (LRP1) Regulates the PDGF Signaling Pathway by Binding the Protein Phosphatase SHP-2 and Modulating SHP-2- Mediated PDGF Signaling Events

et al. 2013

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BackgroundThe PDGF signaling pathway plays a major role in several biological systems, including vascular remodeling that occurs following percutaneous transluminal coronary angioplasty. Recent studies have shown that the LDL receptor-related protein 1 (LRP1) is a physiological regulator of the PDGF signaling pathway. The underlying mechanistic details of how this regulation occurs have yet to be resolved. Activation of the PDGF receptor β (PDGFRβ) leads to tyrosine phosphorylation of the LRP1 cytoplasmic domain within endosomes and generates an LRP1 molecule with increased affinity for adaptor proteins such as SHP-2 that are involved in signaling pathways. SHP-2 is a protein tyrosine phosphatase that positively regulates the PDGFRβ pathway, and is required for PDGF-mediated chemotaxis. We investigated the possibility that LRP1 may regulate the PDGFRβ signaling pathway by binding SHP-2 and competing with the PDGFRβ for this molecule.Methodology/Principal FindingsTo quantify the interaction between SHP-2 and phosphorylated forms of the LRP1 intracellular domain, we utilized an ELISA with purified recombinant proteins. These studies revealed high affinity binding of SHP-2 to phosphorylated forms of both LRP1 intracellular domain and the PDGFRβ kinase domain. By employing the well characterized dynamin inhibitor, dynasore, we established that PDGF-induced SHP-2 phosphorylation primarily occurs within endosomal compartments, the same compartments in which LRP1 is tyrosine phosphorylated by activated PDGFRβ. Immunofluorescence studies revealed colocalization of LRP1 and phospho-SHP-2 following PDGF stimulation of fibroblasts. To define the contribution of LRP1 to SHP-2-mediated PDGF chemotaxis, we employed fibroblasts expressing LRP1 and deficient in LRP1 and a specific SHP-2 inhibitor, NSC-87877. Our results reveal that LRP1 modulates SHP-2-mediated PDGF-mediated chemotaxis.Conclusions/SignificanceOur data demonstrate that phosphorylated forms of LRP1 and PDGFRβ compete for SHP-2 binding, and that expression of LRP1 attenuates SHP-2-mediated PDGF signaling events.

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“…In their dimeric form, PDGFs bind to and activate a PDGF receptor (PDGFR) that consists of two receptor tyrosine kinase subtypes, PDGFR-a and PDGFR-b, localized to the plasma membrane of cells. Once bound to a PDGF, PDGFRs activate diverse signaling molecules and regulatory proteins that contain Src homology 2-domains and thereby elicit various cellular responses like actin reorganization, proliferation, differentiation, or VSMC migration (Jiang et al, 2010;Won et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Chrysanthemum borealeflower floral water inhibits platelet-derived growth factor-stimulated migration and proliferation in vascular smooth muscle cells

Kim

Won

Yoon

et al. 2014

Pharmaceutical Biology

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(2015) Chrysanthemumboreale flower floral water inhibits platelet-derived growth factor-stimulated migration and proliferation in vascular smooth muscle cells, Pharmaceutical Biology, 53:5, 725-734, DOI: 10.3109/13880209.2014 Context: Chrysanthemum boreale Makino (Compositae) (CBM) is a traditional medicine that has been used for the prevention or treatment of various disorders; it has various properties including antioxidation, anti-inflammation, and antitumor. Objective: The present study was designed to explore the in vitro effect of CBM flower floral water (CBMFF) on atherosclerosis-related responses in rat aortic smooth muscle cells (RASMCs). Materials and methods: CBMFF was extracted from CBM flower by steam distillation and analyzed using gas chromatography-mass spectrometry. The anti-atherosclerosis activity of CBMFF was tested by estimating platelet-derived growth factor (PDGF)-BB (10 ng/mL)-induced proliferation and migration levels and intracellular kinase pathways in RASMCs at CBMFF concentrations of 0.01-100 lM and analyzing ex vivo aortic ring assay. Results: Gas chromatography-mass spectrometry showed that the CBMFF contained a total of seven components. The CBMFF inhibits PDGF-BB-stimulated RASMC migration and proliferation (IC 50 : 0.010 lg/mL). Treatment of RASMCs with PDGF-BB induced PDGFR-b phosphorylation and increased the phosphorylations of MAPK p38 and ERK1/2. CBMFF addition prevented PDGF-BBinduced phosphorylation of these kinases (IC 50 : 008 and 0.018 lg/mL, for p38 MAPK and ERK1/ 2, respectively), as well as PDGFR-b (IC 50 : 0.046 lg/mL). Treatment with inhibitors of PDGFR, P38 MAPK, and ERK1/2 decreased PDGF-BB-increased migration and proliferation in RASMCs. Moreover, the CBMFF suppressed PDGF-BB-increased sprout outgrowth of aortic rings (IC 50 : 0.047 lg/mL). Discussion and conclusion: These results demonstrate that CBMFF may inhibit PDGF-BB-induced vascular migration and proliferation, most likely through inhibition of the PDGFR-b-mediated MAPK pathway; therefore, the CBMFF may be promising candidate for the development of herbal remedies for vascular disorders.

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Protein Tyrosine Phosphatase SHP-2 Is Positively Involved in Platelet-Derived Growth Factor–Signaling in Vascular Neointima Formation via the Reactive Oxygen Species–Related Pathway

Cited by 20 publications

References 36 publications

PKCδ Impaired Vessel Formation and Angiogenic Factor Expression in Diabetic Ischemic Limbs

PKCδ Impaired Vessel Formation and Angiogenic Factor Expression in Diabetic Ischemic Limbs

The LDL Receptor-Related Protein 1 (LRP1) Regulates the PDGF Signaling Pathway by Binding the Protein Phosphatase SHP-2 and Modulating SHP-2- Mediated PDGF Signaling Events

Chrysanthemum borealeflower floral water inhibits platelet-derived growth factor-stimulated migration and proliferation in vascular smooth muscle cells

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