Modulation of PKCδ signaling alters the shear stress-mediated increases in endothelial nitric oxide synthase transcription: role of STAT3

Sud, Neetu; Kumar, Sanjiv; Wedgwood, Stephen; Black, Stephen M.

doi:10.1152/ajplung.90534.2008

Cited by 18 publications

(13 citation statements)

References 55 publications

(77 reference statements)

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“…Bryostatin-1 and HGF increase phosphorylation of S727-STAT3 via PKC, and ERK activation, respectively [34, 54]. Here, both mitigated the reduced mitochondrial maximum reserve and respiratory capacity caused by a 4 h FAK14 treatment of bEnd5 cells (Fig.…”

Section: Resultsmentioning

confidence: 89%

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

et al. 2016

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BackgroundSTAT3 is increasingly becoming known for its non-transcriptional regulation of mitochondrial bioenergetic function upon activation of its S727 residue (S727-STAT3). Lengthy mitochondrial dysfunction can lead to cell death. We tested whether an integrin-FAK-STAT3 signaling pathway we recently discovered regulates mitochondrial function and cell survival, and treatments thereof.MethodsCultured mouse brain bEnd5 endothelial cells were treated with integrin, FAK or STAT3 inhibitors, FAK siRNA, as well as integrin and STAT3 activators. STAT3 null cells were transfected with mutant STAT3 plasmids. Outcome measures included oxygen consumption rate for mitochondrial bioenergetics, Western blotting for protein phosphorylation, mitochondrial membrane potential for mitochondrial integrity, ROS production, and cell counts.ResultsVitronectin-dependent mitochondrial basal respiration, ATP production, and maximum reserve and respiratory capacities were suppressed within 4 h by RGD and αvβ3 integrin antagonist peptides. Conversely, integrin ligands vitronectin, laminin and fibronectin stimulated mitochondrial function. Pharmacological inhibition of FAK completely abolished mitochondrial function within 4 h while FAK siRNA treatments confirmed the specificity of FAK signaling. WT, but not S727A functionally dead mutant STAT3, rescued bioenergetics in cells made null for STAT3 using CRISPR-Cas9. STAT3 inhibition with stattic in whole cells rapidly reduced mitochondrial function and mitochondrial pS727-STAT3. Stattic treatment of isolated mitochondria did not reduce pS727 whereas more was detected upon phosphatase inhibition. This suggests that S727-STAT3 is activated in the cytoplasm and is short-lived upon translocation to the mitochondria. FAK inhibition reduced pS727-STAT3 within mitochondria and reduced mitochondrial function in a non-transcriptional manner, as shown by co-treatment with actinomycin. Treatment with the small molecule bryostatin-1 or hepatocyte growth factor (HGF), which indirectly activate S727-STAT3, preserved mitochondrial function during FAK inhibition, but failed in the presence of the STAT3 inhibitor. FAK inhibition induced loss of mitochondrial membrane potential, which was counteracted by bryostatin, and increased superoxide and hydrogen peroxide production. Bryostatin and HGF reduced the substantial cell death caused by FAK inhibition over a 24 h period.ConclusionThese data suggest that extracellular matrix molecules promote STAT3-dependent mitochondrial function and cell survival through integrin-FAK signaling. We furthermore show a new treatment strategy for cell survival using S727-STAT3 activators.

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Section: Resultsmentioning

confidence: 89%

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

et al. 2016

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“…Membranes were immunoblotted with the following antibodies: total Stat3 (C-20), pp42/p44 MAPK (E-4), total p42/p44 MAPK (C-14), all from Santa Cruz Biotechnology; pStat3Ser727 (GE4), phosphotyrosine c-Src (Tyr 416), and c-Src (36D10) from Cell Signaling (Beverly, MA, USA); PR (clone hPRa7), actin (clone ACTN05), and cyclin D1 from Neomarkers (Freemont, CA, USA); and b-tubulin from Sigma. The specificity of pStat3Ser727 (GE4) antibody for western blot (WB) assays was previously reported (Sud et al 2009, Turner et al 2009). Human and mouse Stat3 homologies are completely identical, except for a single amino acid change at position 760 (Pietra et al 1998).…”

Section: Western Blot Analysismentioning

confidence: 99%

p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth

Tkach¹,

Rosemblit²,

Rivas³

et al. 2013

Endocrine-Related Cancer

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Stat3 is a signaling node for multiple oncogenic pathways and is therefore frequently active in breast cancer. As experimental and clinical evidence reveals that progestins are key players in controlling mammary gland tumorigenesis, we studied Stat3 participation in this event.We have previously shown that progestins induce Stat3Tyr705 phosphorylation and its transcriptional activation in breast cancer cells. In this study, we demonstrate that progestins also induce Stat3 phosphorylation at Ser727 residue, which occurs via activation of c-Src/p42/p44 MAPK pathways in murine progestin-dependent C4HD cells and in T-47D cells. Expression of a Stat3S727A vector, which carries a serine-to-alanine substitution at codon 727, shows that Stat3Ser727 phosphorylation is required for full transcriptional activation of cyclin D1 gene expression by progestins and for in vivo Stat3 recruitment on cyclin D1 promoter. Transfection of Stat3S727A in murine and human breast cancer cells abolished progestin-induced in vitro and in vivo growth. Moreover, we found a positive correlation between progesterone receptor expression and nuclear localization of Stat3Ser727 phosphorylation in breast cancer biopsies. These data highlight Stat3 phosphorylation in Ser727 residue as a nongenomic action by progestins, necessary to promote breast cancer growth.

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“…For instance, PKC-␦ inhibits the expression of eNOS via STAT3. In fetal lamb lung, pulmonary artery endothelial cells of fetal lambs shear stress decreases PKC-␦ activity and thus reduces the inhibitory effect of STAT3 on eNOS promoter (553). In addition to eNOS, shear stress may increase pulmonary blood flow in fetal lambs by stimulating inducible NO synthase, perhaps in SMCs (471).…”

Section: Shear Stressmentioning

confidence: 99%

“…The increased phosphorylation of eNOS at Ser-1177 may result from an increased Akt signaling due to the inhibition of PKC-␦ (340). Shear stress has also been shown to upregulate the expression of eNOS through increased phosphorylated c-Jun levels (613) and through reduction in binding of STAT3 to eNOS promoter (553).…”

Section: B Ednomentioning

confidence: 99%

“…Shear stress may acutely stimulate eNOS activity by reducing the inhibitory effect of PKC-␦ on Akt-mediated phosphorylation of eNOS(340). Shear stress may upregulate eNOS expression by activating c-Jun and by relieving the inhibitory effect of STAT3 on eNOS mRNA expression(553,613). Oxygenation may upregulate the expressions and activities of soluble guanylyl cyclase (sGC; Refs.…”

mentioning

confidence: 99%

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Regulation of the Pulmonary Circulation in the Fetus and Newborn

Gao

Raj

2010

Physiological Reviews

298

267

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During the development of the pulmonary vasculature in the fetus, many structural and functional changes occur to prepare the lung for the transition to air breathing. The development of the pulmonary circulation is genetically controlled by an array of mitogenic factors in a temporo-spatial order. With advancing gestation, pulmonary vessels acquire increased vasoreactivity. The fetal pulmonary vasculature is exposed to a low oxygen tension environment that promotes high intrinsic myogenic tone and high vasocontractility. At birth, a dramatic reduction in pulmonary arterial pressure and resistance occurs with an increase in oxygen tension and blood flow. The striking hemodynamic differences in the pulmonary circulation of the fetus and newborn are regulated by various factors and vasoactive agents. Among them, nitric oxide, endothelin-1, and prostaglandin I(2) are mainly derived from endothelial cells and exert their effects via cGMP, cAMP, and Rho kinase signaling pathways. Alterations in these signaling pathways may lead to vascular remodeling, high vasocontractility, and persistent pulmonary hypertension of the newborn.

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Modulation of PKCδ signaling alters the shear stress-mediated increases in endothelial nitric oxide synthase transcription: role of STAT3

Cited by 18 publications

References 55 publications

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

Integrin-FAK signaling rapidly and potently promotes mitochondrial function through STAT3

p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth

Regulation of the Pulmonary Circulation in the Fetus and Newborn

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