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A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus

Myoferlin, a member of ferlin family of proteins, was first discovered as a candidate gene for muscular dystrophy and cardiomyopathy. Recently myoferlin was shown to be also expressed in endothelial and cancer cells where it was shown to modulate VEGFR-2 and EGFR signaling by enhancing their stabili...

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Autores principales: Yadav, Arti, Kumar, Bhavna, Lang, James C., Teknos, Theodoros N, Kumar, Pawan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690845/
https://www.ncbi.nlm.nih.gov/pubmed/28745314
http://dx.doi.org/10.1038/onc.2017.245
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author Yadav, Arti
Kumar, Bhavna
Lang, James C.
Teknos, Theodoros N
Kumar, Pawan
author_facet Yadav, Arti
Kumar, Bhavna
Lang, James C.
Teknos, Theodoros N
Kumar, Pawan
author_sort Yadav, Arti
collection PubMed
description Myoferlin, a member of ferlin family of proteins, was first discovered as a candidate gene for muscular dystrophy and cardiomyopathy. Recently myoferlin was shown to be also expressed in endothelial and cancer cells where it was shown to modulate VEGFR-2 and EGFR signaling by enhancing their stability and recycling. Based on these reports, we hypothesized that myoferlin might be regulating IL-6 signaling by modulating IL-6R stabilization and recycling. However, in our immunoprecipitation (IP) experiments, we did not observe myoferlin binding with IL-6R. Instead, we made a novel discovery that in resting cells myoferlin was bound to EHD2 protein and when cells were treated with IL-6, myoferlin dissociated from EHD2 and binds to activated STAT3. Interestingly, myoferlin depletion did not affect STAT3 phosphorylation, but completely blocked STAT3 translocation to nucleus. In addition, inhibition of STAT3 phosphorylation by phosphorylation defective STAT3 mutants or JAK inhibitor blocked STAT3 binding to myoferlin and nuclear translocation. Myoferlin knockdown significantly decreased IL-6-mediated tumor cell migration, tumorsphere formation and ALDH positive cancer stem cell population, in vitro. Furthermore, myoferlin knockdown significantly decreased IL-6-meditated tumor growth and tumor metastasis. Based on these results, we have proposed a novel model for the role of myoferlin in chaperoning phosphorylated STAT3 to the nucleus.
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spelling pubmed-56908452018-01-24 A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus Yadav, Arti Kumar, Bhavna Lang, James C. Teknos, Theodoros N Kumar, Pawan Oncogene Article Myoferlin, a member of ferlin family of proteins, was first discovered as a candidate gene for muscular dystrophy and cardiomyopathy. Recently myoferlin was shown to be also expressed in endothelial and cancer cells where it was shown to modulate VEGFR-2 and EGFR signaling by enhancing their stability and recycling. Based on these reports, we hypothesized that myoferlin might be regulating IL-6 signaling by modulating IL-6R stabilization and recycling. However, in our immunoprecipitation (IP) experiments, we did not observe myoferlin binding with IL-6R. Instead, we made a novel discovery that in resting cells myoferlin was bound to EHD2 protein and when cells were treated with IL-6, myoferlin dissociated from EHD2 and binds to activated STAT3. Interestingly, myoferlin depletion did not affect STAT3 phosphorylation, but completely blocked STAT3 translocation to nucleus. In addition, inhibition of STAT3 phosphorylation by phosphorylation defective STAT3 mutants or JAK inhibitor blocked STAT3 binding to myoferlin and nuclear translocation. Myoferlin knockdown significantly decreased IL-6-mediated tumor cell migration, tumorsphere formation and ALDH positive cancer stem cell population, in vitro. Furthermore, myoferlin knockdown significantly decreased IL-6-meditated tumor growth and tumor metastasis. Based on these results, we have proposed a novel model for the role of myoferlin in chaperoning phosphorylated STAT3 to the nucleus. 2017-07-24 2017-11-16 /pmc/articles/PMC5690845/ /pubmed/28745314 http://dx.doi.org/10.1038/onc.2017.245 Text en 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
Yadav, Arti
Kumar, Bhavna
Lang, James C.
Teknos, Theodoros N
Kumar, Pawan
A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus
title A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus
title_full A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus
title_fullStr A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus
title_full_unstemmed A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus
title_short A muscle specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus
title_sort muscle specific protein “myoferlin” modulates il-6/stat3 signaling by chaperoning activated stat3 to nucleus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690845/
https://www.ncbi.nlm.nih.gov/pubmed/28745314
http://dx.doi.org/10.1038/onc.2017.245
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