VEGF signaling, mTOR complexes, and the endoplasmic reticulum: Towards a role of metabolic sensing in the regulation of angiogenesis

Evdoxia Karali; Sofia Bellou; Dimitris Stellas; Apostolos Klinakis; Carol Murphy; Theodore Fotsis

doi:10.4161/23723548.2014.964024

VEGF signaling, mTOR complexes, and the endoplasmic reticulum: Towards a role of metabolic sensing in the regulation of angiogenesis

Mol Cell Oncol. 2014 Dec 23;1(3):e964024. doi: 10.4161/23723548.2014.964024. eCollection 2014 Jul-Sep.

Authors

Evdoxia Karali¹, Sofia Bellou², Dimitris Stellas³, Apostolos Klinakis³, Carol Murphy⁴, Theodore Fotsis¹

Affiliations

¹ Foundation of Research and Technology-Hellas; Institute of Molecular Biology & Biotechnology - Department of Biomedical Research; Ioannina, Greece; Laboratory of Biological Chemistry; Medical School; University of Ioannina; Ioannina, Greece.
² Foundation of Research and Technology-Hellas; Institute of Molecular Biology & Biotechnology - Department of Biomedical Research; Ioannina, Greece; Department of Informatics and Telecommunications Engineering; University of Western Macedonia; Kozani, Greece.
³ Department of Cancer Biology; Biomedical Research Foundation of the Academy of Athens ; Athens, Greece.
⁴ Foundation of Research and Technology-Hellas; Institute of Molecular Biology & Biotechnology - Department of Biomedical Research ; Ioannina, Greece.

Abstract

Vascular endothelial growth factor (VEGF) activates unfolded protein response sensors in the endoplasmic reticulum through phospholipase C gamma (PLCγ)-mediated crosstalk with mammalian target of rapamycin complex 1 (mTORC1). Activation of transcription factor 6 (ATF6) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) activate mTORC2, ensuring maximal endothelial cell survival and angiogenic activity through phosphorylation of AKT on Ser473. As mTORC1 is a metabolic sensor, metabolic signals may be integrated with signals from VEGF in the regulation of angiogenesis.

Keywords: AKT; ATF6; CHOP; IRE1α; PERK; PLCγ; VEGF; angiogenesis; apoptosis; mTORC1; mTORC2; survival; unfolded protein response.