EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines

Abstract In epithelial cancers, the epidermal growth factor receptor (EGFR) and integrin α6β4 are frequently overexpressed and found to synergistically activate intracellular signaling pathways that promote cell proliferation and migration. In cancer cells, the β4 subunit is phosphorylated at tyrosi...

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Autores principales:	Lisa te Molder, Maaike Kreft, Niels Heemskerk, Joyce Schuring, Jose M. de Pereda, Kevin Wilhelmsen, Arnoud Sonnenberg
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/87dfb450d8f447a4ac605d2d0ef1c327
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spelling	oai:doaj.org-article:87dfb450d8f447a4ac605d2d0ef1c3272021-12-02T15:27:05ZEGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines10.1038/s41598-021-88134-62045-2322https://doaj.org/article/87dfb450d8f447a4ac605d2d0ef1c3272021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88134-6https://doaj.org/toc/2045-2322Abstract In epithelial cancers, the epidermal growth factor receptor (EGFR) and integrin α6β4 are frequently overexpressed and found to synergistically activate intracellular signaling pathways that promote cell proliferation and migration. In cancer cells, the β4 subunit is phosphorylated at tyrosine residues not normally recognized as kinase substrates; however, the function of these phosphotyrosine residues in cancer cells is a subject of much debate. In EGFR-overexpressing carcinoma cells, we found that the Src family kinase (SFK) inhibitor PP2 reduces β4 tyrosine phosphorylation following the activation of EGFR. However, siRNA mediated knockdown of the SFKs Src, Fyn, Yes and Lyn, individually or in combination, did not affect the EGF-induced phosphorylation of β4. Using phospho-peptide affinity chromatography and mass spectrometry, we found that PLCγ1 binds β4 at the phosphorylated residues Y1422/Y1440, but were unable to verify this interaction in A431 carcinoma cells that overexpress the EGFR. Furthermore, using A431 cells devoid of β4 or reconstituted with phenylalanine specific mutants of β4, the activation of several downstream signaling pathways, including PLCγ/PKC, MAPK and PI3K/Akt, were not substantially affected. We conclude that tyrosine-phosphorylated β4 does not enhance EGFR-mediated signaling in EGFR-overexpressing cells, despite the fact that this integrin subunit is highly tyrosine phosphorylated in these cells.Lisa te MolderMaaike KreftNiels HeemskerkJoyce SchuringJose M. de PeredaKevin WilhelmsenArnoud SonnenbergNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lisa te Molder Maaike Kreft Niels Heemskerk Joyce Schuring Jose M. de Pereda Kevin Wilhelmsen Arnoud Sonnenberg EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines
description	Abstract In epithelial cancers, the epidermal growth factor receptor (EGFR) and integrin α6β4 are frequently overexpressed and found to synergistically activate intracellular signaling pathways that promote cell proliferation and migration. In cancer cells, the β4 subunit is phosphorylated at tyrosine residues not normally recognized as kinase substrates; however, the function of these phosphotyrosine residues in cancer cells is a subject of much debate. In EGFR-overexpressing carcinoma cells, we found that the Src family kinase (SFK) inhibitor PP2 reduces β4 tyrosine phosphorylation following the activation of EGFR. However, siRNA mediated knockdown of the SFKs Src, Fyn, Yes and Lyn, individually or in combination, did not affect the EGF-induced phosphorylation of β4. Using phospho-peptide affinity chromatography and mass spectrometry, we found that PLCγ1 binds β4 at the phosphorylated residues Y1422/Y1440, but were unable to verify this interaction in A431 carcinoma cells that overexpress the EGFR. Furthermore, using A431 cells devoid of β4 or reconstituted with phenylalanine specific mutants of β4, the activation of several downstream signaling pathways, including PLCγ/PKC, MAPK and PI3K/Akt, were not substantially affected. We conclude that tyrosine-phosphorylated β4 does not enhance EGFR-mediated signaling in EGFR-overexpressing cells, despite the fact that this integrin subunit is highly tyrosine phosphorylated in these cells.
format	article
author	Lisa te Molder Maaike Kreft Niels Heemskerk Joyce Schuring Jose M. de Pereda Kevin Wilhelmsen Arnoud Sonnenberg
author_facet	Lisa te Molder Maaike Kreft Niels Heemskerk Joyce Schuring Jose M. de Pereda Kevin Wilhelmsen Arnoud Sonnenberg
author_sort	Lisa te Molder
title	EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines
title_short	EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines
title_full	EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines
title_fullStr	EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines
title_full_unstemmed	EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines
title_sort	egfr-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/87dfb450d8f447a4ac605d2d0ef1c327
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EGFR-dependent tyrosine phosphorylation of integrin β4 is not required for downstream signaling events in cancer cell lines

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