Journal Article

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

Yadav, A, Teknos, T N, Lang, J C, Kumar, P, Kumar, B

2017

Overview

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 vascular endothelial growth factor (VEGFR)-2 and epidermal growth factor receptor (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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/100 / 13/109 / 13/31 / 13/51 / 14/19 / 38/39 / 38/89 / 631/67/395 / 631/80/389/2023 / 64/60 / 82/29 / 82/51 / 96/95 / Animals / Apoptosis / Blotting, Western / Calcium-Binding Proteins - genetics / Calcium-Binding Proteins - metabolism / Cancer / Carcinogenesis / Cardiomyopathy / Carrier Proteins - metabolism / Cell adhesion & migration / Cell Biology / Cell Line, Tumor / Cell migration / Cell Movement - drug effects / Cell Nucleus - metabolism / Cells, Cultured / Cellular proteins / Cellular signal transduction / Epidermal growth factor / Epidermal growth factor receptors / Gene expression / Genetic aspects / Growth factors / Head and Neck Neoplasms - genetics / Head and Neck Neoplasms - metabolism / Head and Neck Neoplasms - pathology / Health aspects / Human Genetics / Humans / Immunoprecipitation / Interleukin 6 / Interleukin-6 - pharmacology / Internal Medicine / Kinases / Medicine / Medicine & Public Health / Membrane Proteins - genetics / Membrane Proteins - metabolism / Metastases / Metastasis / Mice, SCID / Microscopy, Fluorescence / Muscle Proteins - genetics / Muscle Proteins - metabolism / Muscular dystrophy / Nuclear transport / Oncology / original-article / Phosphorylation / Protein binding / Protein Binding - drug effects / Protein Transport - drug effects / Proteins / RNA Interference / Signal Transduction - drug effects / STAT3 / Stat3 protein / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Stem cells / Transplantation, Heterologous / Tumors / Vascular endothelial growth factor / Vascular endothelial growth factor receptors