Predominant expression of the src homology 2-containing tyrosine phosphatase protein SHP2 in vascular smooth muscle cells

Adachi, Masaaki; Iwaki, Hiroaki; Shindoh, Masanobu; Akao, Yukihiro; Hachiya, Takahisa; Ikeda, Masako

doi:10.1007/bf01092755

Cited by 17 publications

(31 citation statements)

References 18 publications

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“…We investigated the effect of insulin (Sigma) and H2O2 on steady-state pHi of ECs and VSMCs in the presence and absence of CO2/HCO 3 Ϫ . For VSMCs, NH 4 ϩ prepulse experiments were performed in the absence of CO2/ HCO 3 Ϫ to estimate the NHE activity. NH4Cl (20 mmol/l) was washed out in a Na ϩ -free solution.…”

Section: Methodsmentioning

confidence: 99%

Insulin inhibits Na⁺/H⁺exchange in vascular smooth muscle and endothelial cells in situ: involvement of H₂O₂and tyrosine phosphatase SHP-2

Boedtkjer¹,

Aalkjær²

2009

American Journal of Physiology-Heart and Circulatory Physiology

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Insulin signals through several intracellular pathways. Here, we tested the hypothesis that insulin modulates Na+/H+ exchange (NHE) activity in vascular cells through H2O2-mediated inhibition of tyrosine phosphatase Src homology 2 domain containing tyrosine phosphatase 2 (SHP-2). We measured intracellular pH (pHi) in isolated mouse mesenteric arteries using fluorescence confocal and wide-field microscopy. In the absence of CO(2)/HCO(3)(-), removal of bath Na(+) produced endothelial acidification (DeltapHi = -0.71 +/- 0.12) inhibited by cariporide. Cariporide reduced endothelial steady-state pHi (DeltapHi=-0.28 +/- 0.08). Insulin and H2O2 acidified endothelial cells 0.2-0.3 pH units and reduced the acidification upon Na+ removal by approximately 65%. Cariporide abolished the effect of insulin and H2O2. In vascular smooth muscle cells, H2O2 produced intracellular acidification (DeltapHi = -0.48 +/- 0.06) as did high concentrations of insulin (DeltapHi = -0.03 +/- 0.01). NHE activity after an NH4+ prepulse was approximately 80% attenuated by H2O2 and approximately 40% by high insulin concentrations. H2O2 had no effect on Na+-HCO3- cotransport activity. NHE1 (slc9a1) was the only plasma membrane NHE isoform detected in mouse mesenteric arteries by RT-PCR analyses. In both cell types, polyethylene glycol catalase abolished the effect of insulin on pHi. Exposure to insulin increased the intracellular concentration of reactive oxygen species estimated with the fluorophore 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein. The SHP-2 selective inhibitor NSC-87877 and protein tyrosine phosphatase (PTP) inhibitor IV reduced steady-state pHi up to 0.3 pH units and inhibited NHE activity 60-80%; when applied in combination with insulin or H2O2, no further effect was obtained. We conclude that NHE contributes to pHi regulation in arterial endothelial and smooth muscle cells in situ and is inhibited by insulin and H2O2. We propose that insulin signaling involves H2O2 and inhibition of PTP SHP-2.

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Section: Methodsmentioning

confidence: 99%

Insulin inhibits Na⁺/H⁺exchange in vascular smooth muscle and endothelial cells in situ: involvement of H₂O₂and tyrosine phosphatase SHP-2

Boedtkjer¹,

Aalkjær²

2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Shp2 and Shp1 are leading candidates for the tyrosine phosphatases. 13 Shp2 is expressed ubiquitously, 14,15 whereas Shp1 expression is more restricted with highest levels in hematopoietic cells. 16 Mice deficient in Shp1 exhibit numerous hematopoietic abnormalities including augmented production and tissue accumulation of granulocytes.…”

Section: Introductionmentioning

confidence: 99%

G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase

Futami

Zhu

Whichard

et al. 2011

Blood

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Src activation involves the coordinated regulation of positive and negative tyrosine phosphorylation sites. The mechanism whereby receptor tyrosine kinases, cytokine receptors, and integrins activate Src is not known. Here, we demonstrate that granulocyte colony-stimulating factor (G-CSF) activates Lyn, the predominant Src kinase in myeloid cells, through Gab2-mediated recruitment of Shp2. After G-CSF stimulation, Lyn dynamically associates with Gab2 in a spatiotemporal manner. The dephosphorylation of phospho-Lyn Tyr507 was abrogated in Shp2-deficient cells transfected with the G-CSF receptor but intact in cells expressing phosphatase-defective Shp2. Auto-phosphorylation of Lyn Tyr396 was impaired in cells treated with Gab2 siRNA. The constitutively activated Shp2E76A directed the dephosphorylation of phospho-Lyn Tyr507 in vitro. Tyr507 did not undergo dephosphorylation in G-CSF–stimulated cells expressing a mutant Gab2 unable to bind Shp2. We propose that Gab2 forms a complex with Lyn and after G-CSF stimulation, Gab2 recruits Shp2, which dephosphorylates phospho-Lyn Tyr507, leading to Lyn activation.

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“…Using immunohistochemical staining and in situ hybridization techniques, Adachi and coworkers have shown ubiquitous expression of SHP2 in VSMCs [17] . Seki and colleagues also reported elevated SHP2 expression in thickened intima in balloon-induced tissue remodeling [18] .…”

Section: General Expression Profiles Of Shp2 In Vsmcsmentioning

confidence: 99%

The role of Src homology 2 containing protein tyrosine phosphatase 2 in vascular smooth muscle cell migration and proliferation

2010

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Vascular smooth muscle cells (VSMCs) perform essential smooth muscle contractile and synthetic functions including migration, differentiation and proliferation under physiological and pathological conditions. In response to pathological stimuli, VMSCs undergo phenotypic change resulting in abnormal migration and proliferation, which may contribute to a "pathogenesis-like" atherosclerosis. Intracellular signaling mechanisms governing this phenotypic switch are of great significance not only for better understanding of atherosclerotic plaque formation but also for strategy for pertinent therapeutic remedies. Src Homology 2 Containing Protein Tyrosine Phosphatase 2 (SHP2) is a ubiquitous tyrosine phosphatase containing Src Homology 2 domains which plays major biological functions in response to various growth factors, hormones or cytokines. In particular, SHP2 is implicated in cell signaling pathways controlling cell cycle progression, growth and migration. In this review we will mainly discuss the recent literature demonstrating the role of SHP2 in VSMC migration and proliferation.

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Predominant expression of the src homology 2-containing tyrosine phosphatase protein SHP2 in vascular smooth muscle cells

Cited by 17 publications

References 18 publications

Insulin inhibits Na⁺/H⁺exchange in vascular smooth muscle and endothelial cells in situ: involvement of H₂O₂and tyrosine phosphatase SHP-2

Insulin inhibits Na⁺/H⁺exchange in vascular smooth muscle and endothelial cells in situ: involvement of H₂O₂and tyrosine phosphatase SHP-2

G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase

The role of Src homology 2 containing protein tyrosine phosphatase 2 in vascular smooth muscle cell migration and proliferation

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Predominant expression of the src homology 2-containing tyrosine phosphatase protein SHP2 in vascular smooth muscle cells

Cited by 17 publications

References 18 publications

Insulin inhibits Na+/H+exchange in vascular smooth muscle and endothelial cells in situ: involvement of H2O2and tyrosine phosphatase SHP-2

Insulin inhibits Na+/H+exchange in vascular smooth muscle and endothelial cells in situ: involvement of H2O2and tyrosine phosphatase SHP-2

G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase

The role of Src homology 2 containing protein tyrosine phosphatase 2 in vascular smooth muscle cell migration and proliferation

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Insulin inhibits Na⁺/H⁺exchange in vascular smooth muscle and endothelial cells in situ: involvement of H₂O₂and tyrosine phosphatase SHP-2

Insulin inhibits Na⁺/H⁺exchange in vascular smooth muscle and endothelial cells in situ: involvement of H₂O₂and tyrosine phosphatase SHP-2