EGF-induced nuclear localization of SHCBP1 activates [beta]-catenin signaling and promotes cancer progression

Aberrant activation of EGFR represents a common event in non-small cell lung carcinoma (NSCLC) and activates various downstream signaling pathways. While EGFR activation of [beta]-catenin signaling was previously reported, the mediating mechanism remains unclear. Our current study found that EGFR activation in NSCLC cells releases SHC-binging protein 1 (SHCBP1) from SHC adaptor protein 1 (SHC1), which subsequently translocates into the nucleus and directly promotes the transactivating activity of [beta]-catenin, consequently resulting in development of NSCLC cell stemness and malignant progression. Furthermore, SHCBP1 promotes [beta]-catenin activity through enhancing the CBP/[beta]-catenin interaction, and most interestingly, a candidate drug that blocks the CBP/[beta]-catenin binding effectively abrogates the aforementioned biological effects of SHCBP1. Clinically, SHCBP1 level in NSCLC tumors was found to inversely correlate with patient survival. Together, our study establishes a novel convergence between EGFR and [beta]-catenin pathways and highlights a potential significance of SHCBP1 as a prognostic biomarker and a therapeutic target.