TIMAP-protein phosphatase 1-complex controls endothelin-1 production via ECE-1 dephosphorylation

Anita Boratkó, Zoltán Veréb, Goran Petrovski, Csilla Csortos

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Endothelin induced signaling pathways can affect blood pressure and vascular tone, but the influence of endothelins on tumor cells is also significant. We have detected elevated endothelin-1 secretion from TIMAP (TGF-β inhibited membrane associated protein) depleted vascular endothelial cells. The autocrine signaling activated by the elevated endothelin-1 level through the ETB receptors evoked an angiogenic-like phenotype, the cells assumed an elongated morphology, and enhanced tube formation and wound healing abilities. The depleted protein, TIMAP, is a highly specific and abundant protein in the endothelial cells, and it is a regulatory/targeting subunit for the catalytic subunit of protein phosphatase 1 (PP1c). Protein-protein interaction between the TIMAP-PP1c complex and the endothelin converting enzyme-1 (ECE-1) was detected, the latter of which is a transmembrane protein that produces the biologically active 21-amino acid form of endothelin-1 from proendothelin. The results indicate that silencing of TIMAP induces a reduction in TIMAP-PP1c activity connected to ECE-1. This leads to an increase in the amount of ECE-1 protein in the plasma membrane and a consequent increase in endothelin-1 secretion. Similarly, activation of PKC, the kinase responsible for ECE-1 phosphorylation increased ECE-1 protein level in the membrane fraction of the endothelial cells. The elevated ECE-1 level was mitigated in time in normal cells, but was clearly preserved in TIMAP-depleted cells. Overall, our results indicate that PKC-phosphorylated ECE-1 is a TIMAP-PP1c substrate and this phosphatase complex has an important role in endothelin-1 production of EC through the regulation of ECE-1 activity.

Original languageEnglish
Pages (from-to)11-18
Number of pages8
JournalInternational Journal of Biochemistry and Cell Biology
Volume73
DOIs
Publication statusPublished - Apr 1 2016

Keywords

  • Endothelial cells
  • Endothelin converting enzyme-1a
  • Endothelin-1
  • Protein phosphatase 1
  • TIMAP

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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