HRS inhibits EGF receptor signaling in the RT4 rat schwannoma cell line

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.