The immunoglobulin‐like domain of neuregulins potentiates ErbB3/HER3 activation and cellular proliferation
The neuregulins (NRGs) represent a large family of membrane‐anchored growth factors, whose deregulation may contribute to the pathogenesis of several tumors. In fact, targeting of NRG‐activated pathways has demonstrated clinical benefit. To improve the efficacy of anti‐NRG therapies, it is essential...
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doaj-57959d67d7e3492398635ae0062734ae2020-11-25T03:49:33ZengWileyMolecular Oncology1574-78911878-02612018-06-011271061107610.1002/1878-0261.12310The immunoglobulin‐like domain of neuregulins potentiates ErbB3/HER3 activation and cellular proliferationAriana Centa0Ruth Rodríguez‐Barrueco1Juan Carlos Montero2Atanasio Pandiella3Instituto de Biología Molecular y Celular del Cáncer IBSAL CSIC and CIBERONC Salamanca SpainInstituto de Biología Molecular y Celular del Cáncer IBSAL CSIC and CIBERONC Salamanca SpainInstituto de Biología Molecular y Celular del Cáncer IBSAL CSIC and CIBERONC Salamanca SpainInstituto de Biología Molecular y Celular del Cáncer IBSAL CSIC and CIBERONC Salamanca SpainThe neuregulins (NRGs) represent a large family of membrane‐anchored growth factors, whose deregulation may contribute to the pathogenesis of several tumors. In fact, targeting of NRG‐activated pathways has demonstrated clinical benefit. To improve the efficacy of anti‐NRG therapies, it is essential to gain insights into the regions of NRGs that favor their pro‐oncogenic properties. Here, we have addressed the protumorigenic impact of different NRG domains. To do this, deletion mutants affecting different NRG domains were expressed in 293 and MCF7 cells. Of the five forms studied, only the wild‐type and a mutant lacking the Ig‐like domain (NRGΔIg) were properly sorted to the plasma membrane. Both forms were released as soluble forms to the culture media. However, the mutant NRGΔIg failed to efficiently activate HER2 and HER3 receptors, signaling pathways, and cell proliferation when compared to wild‐type NRG. Treatment with trastuzumab, a humanized antibody used in the breast cancer clinic, inhibited the constitutive activation of HER2, HER3, and downstream signaling in MCF7 cells constitutively expressing wild‐type NRG. In contrast, this treatment had a marginal effect on MCF7‐NRGΔIg cells. This study demonstrates that the Ig‐like region of NRGs exerts an important role in their capability to activate ErbB/HER receptors and mitogenic responses. Strategies aimed at targeting NRGs should consider that fact to improve neutralization of the pro‐oncogenic properties of NRGs.https://doi.org/10.1002/1878-0261.12310breast cancerHER receptorsIg‐like domainneuregulins |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ariana Centa Ruth Rodríguez‐Barrueco Juan Carlos Montero Atanasio Pandiella |
spellingShingle |
Ariana Centa Ruth Rodríguez‐Barrueco Juan Carlos Montero Atanasio Pandiella The immunoglobulin‐like domain of neuregulins potentiates ErbB3/HER3 activation and cellular proliferation Molecular Oncology breast cancer HER receptors Ig‐like domain neuregulins |
author_facet |
Ariana Centa Ruth Rodríguez‐Barrueco Juan Carlos Montero Atanasio Pandiella |
author_sort |
Ariana Centa |
title |
The immunoglobulin‐like domain of neuregulins potentiates ErbB3/HER3 activation and cellular proliferation |
title_short |
The immunoglobulin‐like domain of neuregulins potentiates ErbB3/HER3 activation and cellular proliferation |
title_full |
The immunoglobulin‐like domain of neuregulins potentiates ErbB3/HER3 activation and cellular proliferation |
title_fullStr |
The immunoglobulin‐like domain of neuregulins potentiates ErbB3/HER3 activation and cellular proliferation |
title_full_unstemmed |
The immunoglobulin‐like domain of neuregulins potentiates ErbB3/HER3 activation and cellular proliferation |
title_sort |
immunoglobulin‐like domain of neuregulins potentiates erbb3/her3 activation and cellular proliferation |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2018-06-01 |
description |
The neuregulins (NRGs) represent a large family of membrane‐anchored growth factors, whose deregulation may contribute to the pathogenesis of several tumors. In fact, targeting of NRG‐activated pathways has demonstrated clinical benefit. To improve the efficacy of anti‐NRG therapies, it is essential to gain insights into the regions of NRGs that favor their pro‐oncogenic properties. Here, we have addressed the protumorigenic impact of different NRG domains. To do this, deletion mutants affecting different NRG domains were expressed in 293 and MCF7 cells. Of the five forms studied, only the wild‐type and a mutant lacking the Ig‐like domain (NRGΔIg) were properly sorted to the plasma membrane. Both forms were released as soluble forms to the culture media. However, the mutant NRGΔIg failed to efficiently activate HER2 and HER3 receptors, signaling pathways, and cell proliferation when compared to wild‐type NRG. Treatment with trastuzumab, a humanized antibody used in the breast cancer clinic, inhibited the constitutive activation of HER2, HER3, and downstream signaling in MCF7 cells constitutively expressing wild‐type NRG. In contrast, this treatment had a marginal effect on MCF7‐NRGΔIg cells. This study demonstrates that the Ig‐like region of NRGs exerts an important role in their capability to activate ErbB/HER receptors and mitogenic responses. Strategies aimed at targeting NRGs should consider that fact to improve neutralization of the pro‐oncogenic properties of NRGs. |
topic |
breast cancer HER receptors Ig‐like domain neuregulins |
url |
https://doi.org/10.1002/1878-0261.12310 |
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