Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis

  • Angiogenesis. 2015 Oct;18(4):449-62. doi: 10.1007/s10456-015-9468-3.
Srimathi Srinivasan  1 ,  Vipul Chitalia  2 ,  Rosana D Meyer  1 ,  Edward Hartsough  1 ,  Manisha Mehta  1 ,  Itrat Harrold  3 ,  Nicole Anderson  3 ,  Hui Feng  3 ,  Lois E H Smith  4 ,  Yan Jiang  5 ,  Catherine E Costello  5 ,  Nader Rahimi  6  7
Affiliations
  • 1. Departments of Pathology and Ophthalmology, Boston University School of Medicine, Boston, MA, 02118, USA.
  • 2. Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.
  • 3. Section of Hematology and Medical Oncology, Department of Pharmacology and Experimental Therapeutics, The Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA.
  • 4. Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 5. Department of Biochemistry and Center for Biomedical Mass Spectrometry, School of Medicine, Boston University Medical Campus, Boston, MA, USA.
  • 6. Departments of Pathology and Ophthalmology, Boston University School of Medicine, Boston, MA, 02118, USA. [email protected].
  • 7. Department of Pathology, Boston University Medical Campus, 670 Albany St., Room 510, Boston, MA, 02118, USA. [email protected].
PMID: 26059764 DOI: 10.1007/s10456-015-9468-3
Abstract

Expression and activation of vascular endothelial growth factor receptor 2 (VEGFR-2) by VEGF ligands are the main events in the stimulation of pathological angiogenesis. VEGFR-2 expression is generally low in the healthy adult blood vessels, but its expression is markedly increased in the pathological angiogenesis. In this report, we demonstrate that phosducin-like 3 (PDCL3), a recently identified chaperone protein involved in the regulation of VEGFR-2 expression, is required for angiogenesis in zebrafish and mouse. PDCL3 undergoes N-terminal methionine acetylation, and this modification affects PDCL3 expression and its interaction with VEGFR-2. Expression of PDCL3 is regulated by hypoxia, the known stimulator of angiogenesis. The mutant PDCL3 that is unable to undergo N-terminal methionine acetylation was refractory to the effect of hypoxia. The siRNA-mediated silencing of PDCL3 decreased VEGFR-2 expression resulting in a decrease in VEGF-induced VEGFR-2 phosphorylation, whereas PDCL3 over-expression increased VEGFR-2 protein. Furthermore, we show that PDCL3 protects VEGFR-2 from misfolding and aggregation. The data provide new insights for the chaperone function of PDCL3 in angiogenesis and the roles of hypoxia and N-terminal methionine acetylation in PDCL3 expression and its effect on VEGFR-2.

Keywords
Angiogenesis; Chaperone protein; Hypoxia; N-terminal methionine acetylation; PDCL3; Protein ubiquitination; VEGFR-2.