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The Phosphatase SHP-2 Activates HIF-1α in Wounds In Vivo by Inhibition of 26S Proteasome Activity

1
Walter Brendel Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-University, Marchioninistr. 27, 81377 Munich, Germany
2
Biomedical Center, Ludwig-Maximilians-University, Großhaderner Str. 9, 82152 Planegg, Germany
3
Medizinische Klinik und Poliklinik I, Klinikum der Universität München, LMU, Marchioninistrasse 15, 81377 Munich, Germany
4
Institute of Pharmacology and Toxicology, Biomedical Center University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany
5
Hospital Pharmacy, Klinikum der Universität München, LMU, Marchioninistrasse 15, 81377 Munich, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(18), 4404; https://doi.org/10.3390/ijms20184404
Received: 27 July 2019 / Revised: 3 September 2019 / Accepted: 5 September 2019 / Published: 7 September 2019
Vascular remodeling and angiogenesis are required to improve the perfusion of ischemic tissues. The hypoxic environment, induced by ischemia, is a potent stimulus for hypoxia inducible factor 1α (HIF-1α) upregulation and activation, which induce pro-angiogenic gene expression. We previously showed that the tyrosine phosphatase SHP-2 drives hypoxia mediated HIF-1α upregulation via inhibition of the proteasomal pathway, resulting in revascularization of wounds in vivo. However, it is still unknown if SHP-2 mediates HIF-1α upregulation by affecting 26S proteasome activity and how the proteasome is regulated upon hypoxia. Using a reporter construct containing the oxygen-dependent degradation (ODD) domain of HIF-1α and a fluorogenic proteasome substrate in combination with SHP-2 mutant constructs, we show that SHP-2 inhibits the 26S proteasome activity in endothelial cells under hypoxic conditions in vitro via Src kinase/p38 mitogen-activated protein kinase (MAPK) signalling. Moreover, the simultaneous expression of constitutively active SHP-2 (E76A) and inactive SHP-2 (CS) in separate hypoxic wounds in the mice dorsal skin fold chamber by localized magnetic nanoparticle-assisted lentiviral transduction showed specific regulation of proteasome activity in vivo. Thus, we identified a new additional mechanism of SHP-2 mediated HIF-1α upregulation and proteasome activity, being functionally important for revascularization of wounds in vivo. SHP-2 may therefore constitute a potential novel therapeutic target for the induction of angiogenesis in ischemic vascular disease. View Full-Text
Keywords: SHP-2; tyrosine phosphatase; HIF-1; 26S proteasome; hypoxia; vascular remodeling; angiogenesis SHP-2; tyrosine phosphatase; HIF-1; 26S proteasome; hypoxia; vascular remodeling; angiogenesis
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Heun, Y.; Grundler Groterhorst, K.; Pogoda, K.; Kraemer, B.F.; Pfeifer, A.; Pohl, U.; Mannell, H. The Phosphatase SHP-2 Activates HIF-1α in Wounds In Vivo by Inhibition of 26S Proteasome Activity. Int. J. Mol. Sci. 2019, 20, 4404.

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