Open AccessProtein tyrosine phosphatase-PEST mediates hypoxia-induced endothelial autophagy and angiogenesis via AMPK activation
Author(s) -
Shivam Chandel,
Amrutha Manikandan,
Nikunj Mehta,
Abel Arul Nathan,
Rakesh Tiwari,
Samar Bhallabha Mohapatra,
Mahesh Chandran,
Abdul Jaleel,
Narayanan Manoj,
Madhulika Dixit
Publication year - 2020
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.250274
Subject(s) - biology , autophagy , angiogenesis , ampk , protein tyrosine phosphatase , hypoxia (environmental) , microbiology and biotechnology , phosphatase , phosphorylation , biochemistry , protein kinase a , cancer research , apoptosis , chemistry , organic chemistry , oxygen
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.