Septin 9 negatively regulates ubiquitin-dependent downregulation of epidermal growth factor receptor

Abstract

Septins constitute a family of GTP-binding proteins involved in a variety of biological processes. Several isoforms have been implicated in disease, but the molecular mechanisms underlying pathogenesis are poorly understood. Here we show that depletion of SEPT9 decreases surface levels of epidermal growth factor receptors (EGFRs) by enhancing receptor degradation. We identify a consensus motif within the SEPT9 aminoterminal domain that supports its association with the adaptor protein CIN85. We further show CIN85-SEPT9 to be localized exclusively to the plasma membrane, where SEPT9 is recruited to EGF-engaged receptors in a CIN85-dependent manner. Finally, we demonstrate that SEPT9 negatively regulates EGFR degradation by preventing association of the ubiquitin ligase Cbl with CIN85 resulting in reduced EGFR ubiquitination. Together, these data provide a mechanistic explanation how SEPT9, though acting exclusively at the plasma membrane, impairs sorting of EGFRs into the degradative pathway.