β-arrestin-1 mediates the endothelin-1-induced activation of Akt and integrin-linked kinase

Roberta Cianfrocca, Laura Rosanò, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Anna Bagnato

Research output: Contribution to journalArticlepeer-review

Abstract

The contribution of the endothelin-1 (ET-1)/ET A receptor (ETAR) axis in tumor growth and progression is investigated in many tumor types, including ovarian carcinoma. In ovarian cancer cells, ET-1 acts as an autocrine growth factor selectively through the ETAR triggering the concomitant activation of multiple pathways. In these cells, the involvement of β-arrestin-1 as signal transducer in ET-1-dependent signalling pathways has been recently highlighted. Because several G protein-coupled receptors have been shown to activate signalling pathways in a β-arrestin-dependent manner, in this study we explored whether β-arrestin-1 is involved in a distinct signalling mechanism linking the ETAR to phosphoinositide 3-kinase (PI3K)/integrin-linked kinase (ILK)/Akt in HEY ovarian cancer cells. The inhibitory effects of ZD4054 (zibotentan), a specific ETAR antagonist, in ET-1-dependent phosphorylation of ILK, Akt, and glycogen synthase kinase (GSK-3b) demonstrated the involvement of the ETAR in these effects. By using a kinase assay, we demonstrate that β-arrestin-1 silencing inhibits the ET-1-induced ILK activity in a time-dependent manner and downstream Akt and GSK-3b phosphorylation. These results reveal that β-arrestin-1 is implicated as an ETAR-transducer in the activation of ILK and Akt and in the inactivation of GSK-3b in response to ET-1 and further support the role of β-arrestin-1 as a multifunctional adaptor facilitating interprotein interactions critically involved in ETAR-mediated signalling that regulate invasive and metastatic behaviour of ovarian cancer.

Original languageEnglish
Pages (from-to)796-801
Number of pages6
JournalCanadian Journal of Physiology and Pharmacology
Volume88
Issue number8
DOIs
Publication statusPublished - Aug 2010

Keywords

  • β-arrestin-1
  • Akt
  • ET-1
  • ETA receptor
  • ILK
  • Ovarian cancer

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Pharmacology

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