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HRS inhibits EGF receptor signaling in the RT4 rat schwannoma cell line
Daniel R Scoles1, Yun Qin, Vu Nguyen
1Rose Moss Neurogenetics Laboratory and Division of Neurology, Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. ScolesD@cshs.org
Abstract:
Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) is required for trafficking of cell surface receptors to the lysosome. Previously, we identified HRS as a protein that interacts with the neurofibromatosis 2 tumor suppressor schwannomin. In the present study, we established modified RT4 schwannoma cell lines that inducibly express HRS and constitutively express epidermal growth factor receptor (EGFR) fused to the green fluorescent protein. We demonstrated that HRS expression reduced EGFR abundance and EGF-mediated Stat3 activation. HRS expression also targeted EGFR to late endosomes. Schwannomin inhibited EGF-mediated Stat3 activation, consistent with HRS and schwannomin interacting in the same signaling pathway. Paradoxically, past studies have shown that HRS overexpression blocked EGFR trafficking to the late endosome and EGFR downregulation contrary to predictions of HRS function in HRS knockout studies. This study is the first to show that HRS can reduce the abundance of total and active EGFR and may reflect cell type-specific HRS function.
Insights
Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) reduces epidermal growth factor receptor (EGFR) levels and signaling. This study reveals a cell-specific function of HRS in EGFR trafficking and degradation.
Area of Science:
- Cell Biology
- Molecular Biology
- Signal Transduction
Background:
- Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) is crucial for lysosomal trafficking of cell surface receptors.
- HRS interacts with schwannomin, a tumor suppressor protein linked to neurofibromatosis type 2.
- Previous studies suggest conflicting roles for HRS in epidermal growth factor receptor (EGFR) trafficking and downregulation.
Purpose of the Study:
- To investigate the role of HRS in EGFR trafficking and signaling in RT4 schwannoma cells.
- To elucidate the functional relationship between HRS, schwannomin, and EGFR signaling.
Main Methods:
- Generation of modified RT4 schwannoma cell lines with inducible HRS expression and constitutive EGFR-green fluorescent protein fusion expression.
- Assessment of EGFR abundance, localization, and EGF-mediated Stat3 activation.
- Evaluation of schwannomin's effect on EGF-mediated Stat3 activation.
Main Results:
- Inducible HRS expression significantly reduced total and active EGFR levels and impaired EGF-mediated Stat3 activation.
- HRS expression promoted the targeting of EGFR to late endosomes.
- Schwannomin inhibited EGF-mediated Stat3 activation, suggesting involvement in the same pathway as HRS.
Conclusions:
- HRS can reduce EGFR abundance and activity, potentially through enhanced lysosomal trafficking.
- The findings highlight a cell type-specific function of HRS in regulating EGFR homeostasis.
- HRS and schwannomin appear to function within the same signaling pathway regulating EGFR.
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