CXCL12 and [N33A]CXCL12 in 5637 and HeLa cells: regulating HER1 phosphorylation via calmodulin/calcineurin.

In the human neoplastic cell lines 5637 and HeLa, recombinant CXCL12 elicited, as expected, downstream signals via both G-protein-dependent and β-arrestin-dependent pathways responsible for inducing a rapid and a late wave, respectively, of ERK1/2 phosphorylation. In contrast, the structural variant...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Antonella Rigo, Michele Gottardi, Ernesto Damiani, Massimiliano Bonifacio, Isacco Ferrarini, Pierluigi Mauri, Fabrizio Vinante
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2012
Materias:
R
Q
Acceso en línea:https://doaj.org/article/743c4843f7da487dbfb1ab698dfca077
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:743c4843f7da487dbfb1ab698dfca077
record_format dspace
spelling oai:doaj.org-article:743c4843f7da487dbfb1ab698dfca0772021-11-18T07:21:51ZCXCL12 and [N33A]CXCL12 in 5637 and HeLa cells: regulating HER1 phosphorylation via calmodulin/calcineurin.1932-620310.1371/journal.pone.0034432https://doaj.org/article/743c4843f7da487dbfb1ab698dfca0772012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22529914/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203In the human neoplastic cell lines 5637 and HeLa, recombinant CXCL12 elicited, as expected, downstream signals via both G-protein-dependent and β-arrestin-dependent pathways responsible for inducing a rapid and a late wave, respectively, of ERK1/2 phosphorylation. In contrast, the structural variant [N33A]CXCL12 triggered no β-arrestin-dependent phosphorylation of ERK1/2, and signaled via G protein-dependent pathways alone. Both CXCL12 and [N33A]CXCL12, however, generated signals that transinhibited HER1 phosphorylation via intracellular pathways. 1) Prestimulation of CXCR4/HER1-positive 5637 or HeLa cells with CXCL12 modified the HB-EGF-dependent activation of HER1 by delaying the peak phosphorylation of tyrosine 1068 or 1173. 2) Prestimulation with the synthetic variant [N33A]CXCL12, while preserving CXCR4-related chemotaxis and CXCR4 internalization, abolished HER1 phosphorylation. 3) In cells knockdown of β-arrestin 2, CXCL12 induced a full inhibition of HER1 like [N33A]CXCL12 in non-silenced cells. 4) HER1 phosphorylation was restored as usual by inhibiting PCK, calmodulin or calcineurin, whereas the inhibition of CaMKII had no discernable effect. We conclude that both recombinant CXCL12 and its structural variant [N33A]CXCL12 may transinhibit HER1 via G-proteins/calmodulin/calcineurin, but [N33A]CXCL12 does not activate β-arrestin-dependent ERK1/2 phosphorylation and retains a stronger inhibitory effect. Therefore, we demonstrated that CXCL12 may influence the magnitude and the persistence of signaling downstream of HER1 in turn involved in the proliferative potential of numerous epithelial cancer. In addition, we recognized that [N33A]CXCL12 activates preferentially G-protein-dependent pathways and is an inhibitor of HER1.Antonella RigoMichele GottardiErnesto DamianiMassimiliano BonifacioIsacco FerrariniPierluigi MauriFabrizio VinantePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 4, p e34432 (2012)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Antonella Rigo
Michele Gottardi
Ernesto Damiani
Massimiliano Bonifacio
Isacco Ferrarini
Pierluigi Mauri
Fabrizio Vinante
CXCL12 and [N33A]CXCL12 in 5637 and HeLa cells: regulating HER1 phosphorylation via calmodulin/calcineurin.
description In the human neoplastic cell lines 5637 and HeLa, recombinant CXCL12 elicited, as expected, downstream signals via both G-protein-dependent and β-arrestin-dependent pathways responsible for inducing a rapid and a late wave, respectively, of ERK1/2 phosphorylation. In contrast, the structural variant [N33A]CXCL12 triggered no β-arrestin-dependent phosphorylation of ERK1/2, and signaled via G protein-dependent pathways alone. Both CXCL12 and [N33A]CXCL12, however, generated signals that transinhibited HER1 phosphorylation via intracellular pathways. 1) Prestimulation of CXCR4/HER1-positive 5637 or HeLa cells with CXCL12 modified the HB-EGF-dependent activation of HER1 by delaying the peak phosphorylation of tyrosine 1068 or 1173. 2) Prestimulation with the synthetic variant [N33A]CXCL12, while preserving CXCR4-related chemotaxis and CXCR4 internalization, abolished HER1 phosphorylation. 3) In cells knockdown of β-arrestin 2, CXCL12 induced a full inhibition of HER1 like [N33A]CXCL12 in non-silenced cells. 4) HER1 phosphorylation was restored as usual by inhibiting PCK, calmodulin or calcineurin, whereas the inhibition of CaMKII had no discernable effect. We conclude that both recombinant CXCL12 and its structural variant [N33A]CXCL12 may transinhibit HER1 via G-proteins/calmodulin/calcineurin, but [N33A]CXCL12 does not activate β-arrestin-dependent ERK1/2 phosphorylation and retains a stronger inhibitory effect. Therefore, we demonstrated that CXCL12 may influence the magnitude and the persistence of signaling downstream of HER1 in turn involved in the proliferative potential of numerous epithelial cancer. In addition, we recognized that [N33A]CXCL12 activates preferentially G-protein-dependent pathways and is an inhibitor of HER1.
format article
author Antonella Rigo
Michele Gottardi
Ernesto Damiani
Massimiliano Bonifacio
Isacco Ferrarini
Pierluigi Mauri
Fabrizio Vinante
author_facet Antonella Rigo
Michele Gottardi
Ernesto Damiani
Massimiliano Bonifacio
Isacco Ferrarini
Pierluigi Mauri
Fabrizio Vinante
author_sort Antonella Rigo
title CXCL12 and [N33A]CXCL12 in 5637 and HeLa cells: regulating HER1 phosphorylation via calmodulin/calcineurin.
title_short CXCL12 and [N33A]CXCL12 in 5637 and HeLa cells: regulating HER1 phosphorylation via calmodulin/calcineurin.
title_full CXCL12 and [N33A]CXCL12 in 5637 and HeLa cells: regulating HER1 phosphorylation via calmodulin/calcineurin.
title_fullStr CXCL12 and [N33A]CXCL12 in 5637 and HeLa cells: regulating HER1 phosphorylation via calmodulin/calcineurin.
title_full_unstemmed CXCL12 and [N33A]CXCL12 in 5637 and HeLa cells: regulating HER1 phosphorylation via calmodulin/calcineurin.
title_sort cxcl12 and [n33a]cxcl12 in 5637 and hela cells: regulating her1 phosphorylation via calmodulin/calcineurin.
publisher Public Library of Science (PLoS)
publishDate 2012
url https://doaj.org/article/743c4843f7da487dbfb1ab698dfca077
work_keys_str_mv AT antonellarigo cxcl12andn33acxcl12in5637andhelacellsregulatingher1phosphorylationviacalmodulincalcineurin
AT michelegottardi cxcl12andn33acxcl12in5637andhelacellsregulatingher1phosphorylationviacalmodulincalcineurin
AT ernestodamiani cxcl12andn33acxcl12in5637andhelacellsregulatingher1phosphorylationviacalmodulincalcineurin
AT massimilianobonifacio cxcl12andn33acxcl12in5637andhelacellsregulatingher1phosphorylationviacalmodulincalcineurin
AT isaccoferrarini cxcl12andn33acxcl12in5637andhelacellsregulatingher1phosphorylationviacalmodulincalcineurin
AT pierluigimauri cxcl12andn33acxcl12in5637andhelacellsregulatingher1phosphorylationviacalmodulincalcineurin
AT fabriziovinante cxcl12andn33acxcl12in5637andhelacellsregulatingher1phosphorylationviacalmodulincalcineurin
_version_ 1718423540426866688