Protein tyrosine phosphatase-PEST mediates hypoxia-induced endothelial autophagy and angiogenesis via AMPK activation
| Autor: | Nikunj Mehta, Madhulika Dixit, Samar Bhallabha Mohapatra, Amrutha Manikandan, Mahesh Chandran, Shivam Chandel, Narayanan Manoj, Abel Arul Nathan, Rakesh Kumar Tiwari, Abdul Jaleel |
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| Rok vydání: | 2020 |
| Předmět: |
animal structures
Angiogenesis Protein Tyrosine Phosphatase Non-Receptor Type 12 Protein tyrosine phosphatase AMP-Activated Protein Kinases Biology environment and public health Vascular remodelling in the embryo Dephosphorylation 03 medical and health sciences 0302 clinical medicine Autophagy Humans Phosphorylation Hypoxia 030304 developmental biology 0303 health sciences fungi Endothelial Cells food and beverages AMPK Cell Biology Cell biology Endothelial stem cell enzymes and coenzymes (carbohydrates) 030220 oncology & carcinogenesis Protein Tyrosine Phosphatases |
| Zdroj: | Journal of Cell Science. |
| ISSN: | 1477-9137 0021-9533 |
| Popis: | Global and endothelial loss of PTP-PEST is associated with impaired cardiovascular development and embryonic lethality. Although hypoxia is implicated in vascular remodelling and angiogenesis, its effect on PTP-PEST remains unexplored. Here we report that hypoxia (1 % oxygen) increases protein levels and catalytic activity of PTP-PEST in primary endothelial cells. Immunoprecipitation followed by mass spectrometry (LC/MS/MS) revealed that alpha subunits of AMPK (α1 and α2) interact with PTP-PEST under normoxia but not in hypoxia. Co-immunoprecipitation experiments confirmed this observation and determined that AMPK α subunits interact with the catalytic domain of PTP-PEST. Knockdown of PTP-PEST abrogated hypoxia mediated tyrosine dephosphorylation and activation of AMPK (Thr172 phosphorylation). Absence of PTP-PEST also blocked hypoxia-induced autophagy (LC3 degradation and puncta formation) which was rescued by AMPK activator, metformin (500 µM). Since endothelial autophagy is a pre-requisite for angiogenesis, knockdown of PTP-PEST also attenuated endothelial cell migration and capillary tube formation with autophagy inducer rapamycin (200 nM) rescuing angiogenesis. In conclusion, this work identifies for the first time PTP-PEST as a regulator of hypoxia-induced AMPK activation and endothelial autophagy to promote angiogenesis. |
| Databáze: | OpenAIRE |
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