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Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis
Many malignancies show increased expression of the EGF receptor family member ErbB3 (HER3). ErbB3 binds beta-1 (HRGβ1), and forms a heterodimer with other ErbB family members, such as ErbB2 (HER2) or EGFR (HER1), enhancing phosphorylation of specific C terminal tyrosine residues and activation of do...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469325/ https://www.ncbi.nlm.nih.gov/pubmed/21725367 http://dx.doi.org/10.1038/onc.2011.275 |
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author | Smirnova, Tatiana Zhou, Zhen Ni Flinn, Rory J. Wyckoff, Jeffrey Boimel, Pamela J. Pozzuto, Maria Coniglio, Salvatore J. Backer, Jonathan M. Bresnick, Anne R. Condeelis, John S. Hynes, Nancy E. Segall, Jeffrey E. |
author_facet | Smirnova, Tatiana Zhou, Zhen Ni Flinn, Rory J. Wyckoff, Jeffrey Boimel, Pamela J. Pozzuto, Maria Coniglio, Salvatore J. Backer, Jonathan M. Bresnick, Anne R. Condeelis, John S. Hynes, Nancy E. Segall, Jeffrey E. |
author_sort | Smirnova, Tatiana |
collection | PubMed |
description | Many malignancies show increased expression of the EGF receptor family member ErbB3 (HER3). ErbB3 binds beta-1 (HRGβ1), and forms a heterodimer with other ErbB family members, such as ErbB2 (HER2) or EGFR (HER1), enhancing phosphorylation of specific C terminal tyrosine residues and activation of downstream signaling pathways. ErbB3 contains six YXXM motifs that bind the p85 subunit of PI3-kinase. Previous studies demonstrated that overexpression of ErbB3 in mammary tumor cells can significantly enhance chemotaxis to HRGβ1 and overall metastatic potential. We tested the hypothesis that ErbB3-mediated PI3-kinase signaling is critical for heregulin-induced motility, and therefore crucial for ErbB3-mediated invasion, intravasation and metastasis. The tyrosines in the six YXXM motifs on the ErbB3 C-terminus were replaced with phenylalanine. In contrast to overexpression of the wild-type ErbB3, overexpression of the mutant ErbB3 did not enhance chemotaxis towards HRGβ1 in vitro or in vivo. We also observed reduced tumor cell motility in the primary tumor by multiphoton microscopy, as well as a dramatically reduced ability of these cells to cross the endothelium and intravasate into the circulation. Moreover, while mutation of the ErbB3 C-terminus had no effect on tumor growth, it had a dramatic effect on spontaneous metastatic potential. Treatment with the PI3-kinase inhibitor PIK-75 similarly inhibited motility and invasion in vitro and in vivo. Our results indicate that stimulation of the early metastatic steps of motility and invasion by ErbB3 requires activation of the PI3-kinase pathway by the ErbB3 receptor. |
format | Online Article Text |
id | pubmed-3469325 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
record_format | MEDLINE/PubMed |
spelling | pubmed-34693252012-10-11 Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis Smirnova, Tatiana Zhou, Zhen Ni Flinn, Rory J. Wyckoff, Jeffrey Boimel, Pamela J. Pozzuto, Maria Coniglio, Salvatore J. Backer, Jonathan M. Bresnick, Anne R. Condeelis, John S. Hynes, Nancy E. Segall, Jeffrey E. Oncogene Article Many malignancies show increased expression of the EGF receptor family member ErbB3 (HER3). ErbB3 binds beta-1 (HRGβ1), and forms a heterodimer with other ErbB family members, such as ErbB2 (HER2) or EGFR (HER1), enhancing phosphorylation of specific C terminal tyrosine residues and activation of downstream signaling pathways. ErbB3 contains six YXXM motifs that bind the p85 subunit of PI3-kinase. Previous studies demonstrated that overexpression of ErbB3 in mammary tumor cells can significantly enhance chemotaxis to HRGβ1 and overall metastatic potential. We tested the hypothesis that ErbB3-mediated PI3-kinase signaling is critical for heregulin-induced motility, and therefore crucial for ErbB3-mediated invasion, intravasation and metastasis. The tyrosines in the six YXXM motifs on the ErbB3 C-terminus were replaced with phenylalanine. In contrast to overexpression of the wild-type ErbB3, overexpression of the mutant ErbB3 did not enhance chemotaxis towards HRGβ1 in vitro or in vivo. We also observed reduced tumor cell motility in the primary tumor by multiphoton microscopy, as well as a dramatically reduced ability of these cells to cross the endothelium and intravasate into the circulation. Moreover, while mutation of the ErbB3 C-terminus had no effect on tumor growth, it had a dramatic effect on spontaneous metastatic potential. Treatment with the PI3-kinase inhibitor PIK-75 similarly inhibited motility and invasion in vitro and in vivo. Our results indicate that stimulation of the early metastatic steps of motility and invasion by ErbB3 requires activation of the PI3-kinase pathway by the ErbB3 receptor. 2011-07-04 2012-02-09 /pmc/articles/PMC3469325/ /pubmed/21725367 http://dx.doi.org/10.1038/onc.2011.275 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Smirnova, Tatiana Zhou, Zhen Ni Flinn, Rory J. Wyckoff, Jeffrey Boimel, Pamela J. Pozzuto, Maria Coniglio, Salvatore J. Backer, Jonathan M. Bresnick, Anne R. Condeelis, John S. Hynes, Nancy E. Segall, Jeffrey E. Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis |
title | Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis |
title_full | Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis |
title_fullStr | Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis |
title_full_unstemmed | Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis |
title_short | Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis |
title_sort | phosphoinositide 3-kinase signaling is critical for erbb3-driven breast cancer cell motility and metastasis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469325/ https://www.ncbi.nlm.nih.gov/pubmed/21725367 http://dx.doi.org/10.1038/onc.2011.275 |
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