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The Insulin Resistance Grb14 Adaptor Protein Promotes Thyroid Cancer Ret Signaling and Progression
The growth factor receptor-bound protein (Grb) 14 is an adapter molecule of the Grb7/10/14 family with characteristic BPS domains serving to avidly bind tyrosine kinases. Grb14 inhibits insulin receptor (IR) catalytic activity through interaction with the BPS domain and impedes peptide substrate bin...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954818/ https://www.ncbi.nlm.nih.gov/pubmed/22158039 http://dx.doi.org/10.1038/onc.2011.569 |
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author | Balogh, Katalin Asa, Sylvia L. Zheng, Lei Cassol, Clarissa Cheng, Sonia Ezzat, Shereen |
author_facet | Balogh, Katalin Asa, Sylvia L. Zheng, Lei Cassol, Clarissa Cheng, Sonia Ezzat, Shereen |
author_sort | Balogh, Katalin |
collection | PubMed |
description | The growth factor receptor-bound protein (Grb) 14 is an adapter molecule of the Grb7/10/14 family with characteristic BPS domains serving to avidly bind tyrosine kinases. Grb14 inhibits insulin receptor (IR) catalytic activity through interaction with the BPS domain and impedes peptide substrate binding. Members of this Grb family have also been shown to interact with other kinases through their SH2 domain. Here we examined the functional role of Grb14 in thyroid cancer using loss- and gain-of-function approaches. Stable knockdown of Grb14 in thyroid cancer cells facilitated insulin receptor signaling. In contrast, RET phosphorylation was diminished in concert with reduced activation of Akt and STAT3. Loss of Grb14 also resulted in diminished cell proliferation and invasion both in vitro and in mouse flank xenografts. In complementary studies, forced expression of Grb14 interrupted insulin receptor signaling but facilitated RET activation, STAT3, and Akt phosphorylation. Consistent with these findings Grb14 over-expression enhanced cell invasion and resulted in striking metastases in an orthotopic thyroid cancer mouse xenograft model. Primary human thyroid cancer microarrays revealed a positive correlation between Grb14 expression and invasive behavior. Our findings uncover a new role for Grb14 in finely tuning receptor signaling and modulating thyroid cancer progression. |
format | Online Article Text |
id | pubmed-3954818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
record_format | MEDLINE/PubMed |
spelling | pubmed-39548182014-03-14 The Insulin Resistance Grb14 Adaptor Protein Promotes Thyroid Cancer Ret Signaling and Progression Balogh, Katalin Asa, Sylvia L. Zheng, Lei Cassol, Clarissa Cheng, Sonia Ezzat, Shereen Oncogene Article The growth factor receptor-bound protein (Grb) 14 is an adapter molecule of the Grb7/10/14 family with characteristic BPS domains serving to avidly bind tyrosine kinases. Grb14 inhibits insulin receptor (IR) catalytic activity through interaction with the BPS domain and impedes peptide substrate binding. Members of this Grb family have also been shown to interact with other kinases through their SH2 domain. Here we examined the functional role of Grb14 in thyroid cancer using loss- and gain-of-function approaches. Stable knockdown of Grb14 in thyroid cancer cells facilitated insulin receptor signaling. In contrast, RET phosphorylation was diminished in concert with reduced activation of Akt and STAT3. Loss of Grb14 also resulted in diminished cell proliferation and invasion both in vitro and in mouse flank xenografts. In complementary studies, forced expression of Grb14 interrupted insulin receptor signaling but facilitated RET activation, STAT3, and Akt phosphorylation. Consistent with these findings Grb14 over-expression enhanced cell invasion and resulted in striking metastases in an orthotopic thyroid cancer mouse xenograft model. Primary human thyroid cancer microarrays revealed a positive correlation between Grb14 expression and invasive behavior. Our findings uncover a new role for Grb14 in finely tuning receptor signaling and modulating thyroid cancer progression. 2011-12-12 2012-09-06 /pmc/articles/PMC3954818/ /pubmed/22158039 http://dx.doi.org/10.1038/onc.2011.569 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 Balogh, Katalin Asa, Sylvia L. Zheng, Lei Cassol, Clarissa Cheng, Sonia Ezzat, Shereen The Insulin Resistance Grb14 Adaptor Protein Promotes Thyroid Cancer Ret Signaling and Progression |
title | The Insulin Resistance Grb14 Adaptor Protein Promotes Thyroid Cancer Ret Signaling and Progression |
title_full | The Insulin Resistance Grb14 Adaptor Protein Promotes Thyroid Cancer Ret Signaling and Progression |
title_fullStr | The Insulin Resistance Grb14 Adaptor Protein Promotes Thyroid Cancer Ret Signaling and Progression |
title_full_unstemmed | The Insulin Resistance Grb14 Adaptor Protein Promotes Thyroid Cancer Ret Signaling and Progression |
title_short | The Insulin Resistance Grb14 Adaptor Protein Promotes Thyroid Cancer Ret Signaling and Progression |
title_sort | insulin resistance grb14 adaptor protein promotes thyroid cancer ret signaling and progression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954818/ https://www.ncbi.nlm.nih.gov/pubmed/22158039 http://dx.doi.org/10.1038/onc.2011.569 |
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