Beta-arrestin-1 mediates the endothelin-1-induced activation of Akt and integrin-linked kinase.
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.
Cianfrocca
Roberta
R
Laboratory of Molecular Pathology, Regina Elena Cancer Institute, via Delle Messi D'Oro 156, Rome, Italy.
Rosanò
Laura
L
Spinella
Francesca
F
Di Castro
Valeriana
V
Natali
Pier Giorgio
PG
Bagnato
Anna
A
D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008954:Models, Biological; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D000099200:Scaffold Protein ILK
D019390:Arrestins; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011759:Pyrrolidines; D034741:RNA, Small Interfering; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D000099200:Scaffold Protein ILK; C000605253:ARRB1 protein, human; C511404:ZD4054; C000605506:GSK3B protein, human