GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.

Kisspeptins (Kp), peptide products of the Kisspeptin-1 (KISS1) gene are endogenous ligands for a G protein-coupled receptor 54 (GPR54). Previous findings have shown that KISS1 acts as a metastasis suppressor in numerous cancers in humans. However, recent studies have demonstrated that an increase in...

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Main Authors: Mateusz Zajac, Jeffrey Law, Dragana Donna Cvetkovic, Macarena Pampillo, Lindsay McColl, Cynthia Pape, Gianni M Di Guglielmo, Lynne M Postovit, Andy V Babwah, Moshmi Bhattacharya
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2011-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3125256?pdf=render
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author Mateusz Zajac
Jeffrey Law
Dragana Donna Cvetkovic
Macarena Pampillo
Lindsay McColl
Cynthia Pape
Gianni M Di Guglielmo
Lynne M Postovit
Andy V Babwah
Moshmi Bhattacharya
author_facet Mateusz Zajac
Jeffrey Law
Dragana Donna Cvetkovic
Macarena Pampillo
Lindsay McColl
Cynthia Pape
Gianni M Di Guglielmo
Lynne M Postovit
Andy V Babwah
Moshmi Bhattacharya
author_sort Mateusz Zajac
collection DOAJ
description Kisspeptins (Kp), peptide products of the Kisspeptin-1 (KISS1) gene are endogenous ligands for a G protein-coupled receptor 54 (GPR54). Previous findings have shown that KISS1 acts as a metastasis suppressor in numerous cancers in humans. However, recent studies have demonstrated that an increase in KISS1 and GPR54 expression in human breast tumors correlates with higher tumor grade and metastatic potential. At present, whether or not Kp signaling promotes breast cancer cell invasiveness, required for metastasis and the underlying mechanisms, is unknown. We have found that kisspeptin-10 (Kp-10), the most potent Kp, stimulates the invasion of human breast cancer MDA-MB-231 and Hs578T cells using Matrigel-coated Transwell chamber assays and induces the formation of invasive stellate structures in three-dimensional invasion assays. Furthermore, Kp-10 stimulated an increase in matrix metalloprotease (MMP)-9 activity. We also found that Kp-10 induced the transactivation of epidermal growth factor receptor (EGFR). Knockdown of the GPCR scaffolding protein, β-arrestin 2, inhibited Kp-10-induced EGFR transactivation as well as Kp-10 induced invasion of breast cancer cells via modulation of MMP-9 secretion and activity. Finally, we found that the two receptors associate with each other under basal conditions, and FRET analysis revealed that GPR54 interacts directly with EGFR. The stability of the receptor complex formation was increased upon treatment of cells by Kp-10. Taken together, our findings suggest a novel mechanism by which Kp signaling via GPR54 stimulates breast cancer cell invasiveness.
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spelling doaj.art-5a69fdac4b1d42f0b509bfcdf2b092862022-12-22T02:29:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0166e2159910.1371/journal.pone.0021599GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.Mateusz ZajacJeffrey LawDragana Donna CvetkovicMacarena PampilloLindsay McCollCynthia PapeGianni M Di GuglielmoLynne M PostovitAndy V BabwahMoshmi BhattacharyaKisspeptins (Kp), peptide products of the Kisspeptin-1 (KISS1) gene are endogenous ligands for a G protein-coupled receptor 54 (GPR54). Previous findings have shown that KISS1 acts as a metastasis suppressor in numerous cancers in humans. However, recent studies have demonstrated that an increase in KISS1 and GPR54 expression in human breast tumors correlates with higher tumor grade and metastatic potential. At present, whether or not Kp signaling promotes breast cancer cell invasiveness, required for metastasis and the underlying mechanisms, is unknown. We have found that kisspeptin-10 (Kp-10), the most potent Kp, stimulates the invasion of human breast cancer MDA-MB-231 and Hs578T cells using Matrigel-coated Transwell chamber assays and induces the formation of invasive stellate structures in three-dimensional invasion assays. Furthermore, Kp-10 stimulated an increase in matrix metalloprotease (MMP)-9 activity. We also found that Kp-10 induced the transactivation of epidermal growth factor receptor (EGFR). Knockdown of the GPCR scaffolding protein, β-arrestin 2, inhibited Kp-10-induced EGFR transactivation as well as Kp-10 induced invasion of breast cancer cells via modulation of MMP-9 secretion and activity. Finally, we found that the two receptors associate with each other under basal conditions, and FRET analysis revealed that GPR54 interacts directly with EGFR. The stability of the receptor complex formation was increased upon treatment of cells by Kp-10. Taken together, our findings suggest a novel mechanism by which Kp signaling via GPR54 stimulates breast cancer cell invasiveness.http://europepmc.org/articles/PMC3125256?pdf=render
spellingShingle Mateusz Zajac
Jeffrey Law
Dragana Donna Cvetkovic
Macarena Pampillo
Lindsay McColl
Cynthia Pape
Gianni M Di Guglielmo
Lynne M Postovit
Andy V Babwah
Moshmi Bhattacharya
GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.
PLoS ONE
title GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.
title_full GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.
title_fullStr GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.
title_full_unstemmed GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.
title_short GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.
title_sort gpr54 kiss1r transactivates egfr to promote breast cancer cell invasiveness
url http://europepmc.org/articles/PMC3125256?pdf=render
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