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

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 beta-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 beta-arrestin-dependent manner, in this study we explored whether beta-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-3beta) demonstrated the involvement of the ETAR in these effects. By using a kinase assay, we demonstrate that beta-arrestin-1 silencing inhibits the ET-1-induced ILK activity in a time-dependent manner and downstream Akt and GSK-3beta phosphorylation. These results reveal that beta-arrestin-1 is implicated as an ETAR-transducer in the activation of ILK and Akt and in the inactivation of GSK-3beta in response to ET-1 and further support the role of beta-arrestin-1 as a multifunctional adaptor facilitating interprotein interactions critically involved in ETAR-mediated signalling that regulate invasive and metastatic behaviour of ovarian cancer.

• Authors: Roberta Cianfrocca, Laura Rosanò, Francesca Spinella, Valeriana Di Castro, Pier Giorgio Natali, Anna Bagnato
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 88 Issue 8 Pg. 796-801 (Aug 2010) ISSN: 1205-7541 [Electronic] Canada
• PMID: 20725137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARRB1 protein, human
• Arrestins
• Endothelin A Receptor Antagonists
• Endothelin-1
• Pyrrolidines
• RNA, Small Interfering
• ZD4054
• beta-Arrestin 1
• beta-Arrestins
• integrin-linked kinase
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Arrestins (genetics, metabolism)
• Cell Line, Tumor
• Endothelin A Receptor Antagonists
• Endothelin-1 (pharmacology)
• Enzyme Activation (drug effects)
• Female
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Models, Biological
• Ovarian Neoplasms (metabolism, pathology)
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrrolidines (pharmacology)
• RNA, Small Interfering (genetics)
• Signal Transduction (drug effects, physiology)
• beta-Arrestin 1
• beta-Arrestins