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SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is a predominantly pediatric soft-tissue cancer where the tumor cells exhibit characteristics of the developing skeletal muscle, and the two most common sub-types are embryonal and alveolar RMS. Elevated activation of the receptor tyrosine kinase (RTK) MET is frequent in RMS a...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833614/ https://www.ncbi.nlm.nih.gov/pubmed/29445192 http://dx.doi.org/10.1038/s41419-018-0261-2 |
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author | Saini, Masum Verma, Aakanksha Mathew, Sam J. |
author_facet | Saini, Masum Verma, Aakanksha Mathew, Sam J. |
author_sort | Saini, Masum |
collection | PubMed |
description | Rhabdomyosarcoma (RMS) is a predominantly pediatric soft-tissue cancer where the tumor cells exhibit characteristics of the developing skeletal muscle, and the two most common sub-types are embryonal and alveolar RMS. Elevated activation of the receptor tyrosine kinase (RTK) MET is frequent in RMS and is thought to cause increased tumor metastasis and lack of differentiation. However, the reasons underlying dysregulated MET expression and activation in RMS are not well understood. Therefore, we explored the role of Sprouty 2 (SPRY2), a modulator of RTK signaling, in regulating MET. We identify SPRY2 as a novel MET interactor that colocalizes with and binds MET in both embryonal and alveolar RMS. We find that depletion of SPRY2 leads to MET degradation, resulting in reduced migratory and clonogenic potential, and induction of differentiation in both embryonal and alveolar RMS, outcomes that are identical to depletion of MET. Activation of the ERK/MAPK pathway, known to be crucial for regulating cell migration and whose inhibition is required for myogenic differentiation, was downregulated upon depletion of MET or SPRY2. This provides a direct connection to the decreased migration and induction of differentiation upon depletion of MET or SPRY2. Thus, these data indicate that SPRY2 interacts with MET and stabilizes it in order to maintain signaling downstream of MET, which keeps the ERK/MAPK pathway active, resulting in metastatic potential and inhibition of differentiation in RMS. Our results identify a novel mechanism by which MET signaling is stabilized in RMS, and is a potential target for therapeutic intervention in RMS. |
format | Online Article Text |
id | pubmed-5833614 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58336142018-03-05 SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma Saini, Masum Verma, Aakanksha Mathew, Sam J. Cell Death Dis Article Rhabdomyosarcoma (RMS) is a predominantly pediatric soft-tissue cancer where the tumor cells exhibit characteristics of the developing skeletal muscle, and the two most common sub-types are embryonal and alveolar RMS. Elevated activation of the receptor tyrosine kinase (RTK) MET is frequent in RMS and is thought to cause increased tumor metastasis and lack of differentiation. However, the reasons underlying dysregulated MET expression and activation in RMS are not well understood. Therefore, we explored the role of Sprouty 2 (SPRY2), a modulator of RTK signaling, in regulating MET. We identify SPRY2 as a novel MET interactor that colocalizes with and binds MET in both embryonal and alveolar RMS. We find that depletion of SPRY2 leads to MET degradation, resulting in reduced migratory and clonogenic potential, and induction of differentiation in both embryonal and alveolar RMS, outcomes that are identical to depletion of MET. Activation of the ERK/MAPK pathway, known to be crucial for regulating cell migration and whose inhibition is required for myogenic differentiation, was downregulated upon depletion of MET or SPRY2. This provides a direct connection to the decreased migration and induction of differentiation upon depletion of MET or SPRY2. Thus, these data indicate that SPRY2 interacts with MET and stabilizes it in order to maintain signaling downstream of MET, which keeps the ERK/MAPK pathway active, resulting in metastatic potential and inhibition of differentiation in RMS. Our results identify a novel mechanism by which MET signaling is stabilized in RMS, and is a potential target for therapeutic intervention in RMS. Nature Publishing Group UK 2018-02-14 /pmc/articles/PMC5833614/ /pubmed/29445192 http://dx.doi.org/10.1038/s41419-018-0261-2 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Saini, Masum Verma, Aakanksha Mathew, Sam J. SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma |
title | SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma |
title_full | SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma |
title_fullStr | SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma |
title_full_unstemmed | SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma |
title_short | SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma |
title_sort | spry2 is a novel met interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833614/ https://www.ncbi.nlm.nih.gov/pubmed/29445192 http://dx.doi.org/10.1038/s41419-018-0261-2 |
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