A CD109-SMURF2 Axis Diverts EGFR from Degradation to Sustain Oncogenic Signaling and Promote Squamous Cell Carcinoma Invasion and Stemness

Abstract

Squamous cell carcinoma (SCC) remains difficult to treat, particularly in recurrent or metastatic disease. Although EGFR signaling is a well-established driver of SCC pathogenesis, mechanisms regulating its activity remain incompletely understood. CD109, a GPI-anchored glycoprotein frequently overexpressed in SCC, has been implicated in EGFR signaling, but its mechanisms remain poorly defined. Here, we show that CD109 is elevated in head and neck SCC (HNSCC) in the TCGA PanCancer Atlas and significantly correlates with reduced disease-free survival. Integrative transcriptomic (TCGA PanCancer Atlas) and proteomic (LinkedOmics) analyses revealed strong positive correlations between CD109, EGFR, and SMURF2. These findings were further validated by immunohistochemistry in HNSCC patient samples. Mechanistically, CD109 overexpression impaired EGFR degradation, suppressed degradation-associated EGFR pY1045 phosphorylation, and enhanced signaling-associated pY1068 phosphorylation, resulting in increased STAT3, AKT, and ERK signaling. We identify SMURF2 as a mediator of these effects, with CD109 promoting EGFR-SMURF2 complex formation. SMURF2 gain- and loss-of-function studies in SCC cells, demonstrated that SMURF2 stabilizes EGFR by reducing EGFR interaction with the ubiquitin ligase c-Cbl, thereby limiting EGFR turnover in a CD109-dependent manner. Functionally, the CD109-SMURF2-EGFR axis promotes EGF-induced stemness, invasion, and proliferation in SCC cells. Together, these findings identify CD109 as a molecular switch controlling EGFR fate by redirecting EGFR from c-Cbl-mediated degradation toward SMURF2-dependent stabilization, sustaining oncogenic signaling. This previously unrecognized regulatory pathway reveals the CD109-SMURF2 axis as a vulnerability with potential for targeted intervention in EGFR-driven SCCs.