Regulation of Cellular Levels of Sprouty2 Protein by Prolyl Hydroxylase Domain and von Hippel-Lindau Proteins

Anderson, Kathryn B.; Nordquist, Kyle A.; Gao, Xianlong; Hicks, Kristin C.; Zhai, Bo; Gygi, Steven P.; Patel, Tarun B.

doi:10.1074/jbc.m111.303222

Cited by 52 publications

(54 citation statements)

References 59 publications

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“…15). Together with data from a previous study demonstrating that hypoxia regulates Sprouty proteins by prolyl hydroxylases [145], these results point to hypoxia as a general posttranscriptional stimulus for SPRY2. In vivo, hypoxia-induced SPRY2 expression may provide a protective homeostatic function when the vasculature is exposed to hypoxia.…”

Section: Increased Spry2 Expression At High Cell Densities -Hypoxia supporting

confidence: 54%

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Sprouty2 expression controls endothelial monolayer integrity and quiescence

et al. 2012

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Section: Increased Spry2 Expression At High Cell Densities -Hypoxia supporting

confidence: 54%

“…Therefore, cells have restricted possibilities to control SPRY2 function: by regulating its abundance [143][144][145], its localization [10,123], and/or its post-transcriptional modifications [119,126,170]. Here we show, that in primary endothelial cells, SPRY2…”

Section: Spry2 Expression Increases With Higher Cell Densitymentioning

confidence: 75%

Sprouty2 expression controls endothelial monolayer integrity and quiescence

et al. 2012

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“…Two recent observations are relevant to the intervertebral niche. Anderson et al (36) showed that PHDs mediate hydroxylation and degradation of Spry2, a modulator of receptor tyrosine kinases that, in this case, may control growth factor signaling. In another study, Walmsley et al (37) noted that PHD3 regulated neutrophil survival by modulating antiapoptotic molecules in hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Expression of Prolyl Hydroxylases (PHDs) Is Selectively Controlled by HIF-1 and HIF-2 Proteins in Nucleus Pulposus Cells of the Intervertebral Disc

Fujita

Markova

Anderson

et al. 2012

Journal of Biological Chemistry

102

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Background: Regulation of PHD expression and their function in hypoxia is unknown in nucleus pulposus. Results: Expression of PHD1-3 is regulated differentially by HIF-1/2. Under hypoxia, PHD2 degrades HIF-1␣, whereas PHD3 promotes its activity. Conclusion:In hypoxic nucleus pulposus, HIFs and PHDs constitute a regulatory network. Significance: PHD2 and 3 may serve as oxygen sensors in the intervertebral disc.

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“…However, recently other PHD targets such as IB kinase, activating transcription factor 4, or sprouty2 have been identified that might be affected in our nPhd2 ⌬/⌬ mice. [27][28][29] Furthermore, because PHD2 is negatively regulated by the peptidyl-prolyl cis/trans isomerase FKBP38, 30,31 which in turn interacts with presenilins 32 known to be involved in neurodegenerative processes, neuronal PHD2 deletion might influence neuronal cell fate by an hypoxiaindependent mechanism. Nevertheless, the robust increase in HIF-␣ proteins and HIF target gene expression known to confer neuroprotection strongly indicate the involvement of the PHD-HIF axis.…”

Section: Involvement Of the Hif Pathwaymentioning

confidence: 99%

Neuron-Specific Prolyl-4-Hydroxylase Domain 2 Knockout Reduces Brain Injury After Transient Cerebral Ischemia

Kunze

Zhou

Veltkamp

et al. 2012

Stroke

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Background and Purpose-Numerous factors involved in the adaptive response to hypoxia, including erythropoietin and vascular endothelial growth factor are transcriptionally regulated by hypoxia-inducible factors (HIFs). During normoxia, prolyl-4-hydroxylase domain (PHD) proteins hydroxylate HIF-␣ subunits, resulting in their degradation. We investigated the effect of neuronal deletion of PHD2, the most abundant isoform in brain, for stroke outcome. Methods-We generated neuron-specific Phd2 knockout mice and subjected animals to systemic hypoxia or transient middle cerebral artery occlusion. Infarct volume and cell death were determined by histology. HIF-1␣, HIF-2␣, and HIF target genes were analyzed by immunoblotting and real-time polymerase chain reaction, respectively. Results-Neuron-specific ablation of Phd2 significantly increased protein stability of HIF-1␣ and HIF-2␣ in the forebrain and enhanced expression of the neuroprotective HIF target genes erythropoietin and vascular endothelial growth factor as well as glucose transporter and glycolysis-related enzymes under hypoxic and ischemic conditions. Mice with Phd2-deficient neurons subjected to transient cerebral ischemia exhibited a strong reduction in infarct size, and cell death of hippocampal CA1 neurons located in the peri-infarct region was dramatically reduced in these mice. Vessel density in forebrain subregions, except for caudate-putamen, was not altered in Phd2-deficient animals. Conclusions-Our findings denote that the endogenous adaptive response on hypoxic-ischemic insults in the brain is at least partly dependent on the activity of HIFs and identify PHD2 as the key regulator for the protective hypoxia response. The results suggest that specific inhibition of PHD2 may provide a useful therapeutic strategy to protect brain tissue from ischemic injury. (Stroke. 2012;43:2748-2756.)

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Regulation of Cellular Levels of Sprouty2 Protein by Prolyl Hydroxylase Domain and von Hippel-Lindau Proteins

Cited by 52 publications

References 59 publications

Sprouty2 expression controls endothelial monolayer integrity and quiescence

Sprouty2 expression controls endothelial monolayer integrity and quiescence

Expression of Prolyl Hydroxylases (PHDs) Is Selectively Controlled by HIF-1 and HIF-2 Proteins in Nucleus Pulposus Cells of the Intervertebral Disc

Neuron-Specific Prolyl-4-Hydroxylase Domain 2 Knockout Reduces Brain Injury After Transient Cerebral Ischemia

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