EGF-induced nuclear localization of SHCBP1 activates β-catenin signaling and promotes cancer progression.

Abstract

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 β-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 β-catenin, consequently resulting in development of NSCLC cell stemness and malignant progression. Furthermore, SHCBP1 promotes β-catenin activity through enhancing the CBP/β-catenin interaction, and most interestingly, a candidate drug that blocks the CBP/β-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 β-catenin pathways and highlights a potential significance of SHCBP1 as a prognostic biomarker and a therapeutic target.

• Authors: Lei Liu, Yi Yang, Shihua Liu, Tianyu Tao, Junchao Cai, Jueheng Wu, Hongyu Guan, Xun Zhu, Zhenjian He, Jun Li, Erwei Song, Musheng Zeng, Mengfeng Li
• Journal: Oncogene (Oncogene) Vol. 38 Issue 5 Pg. 747-764 (01 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 30177836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CTNNB1 protein, human
• Neoplasm Proteins
• SHCBP1 protein, human
• Shc Signaling Adaptor Proteins
• beta Catenin
• Epidermal Growth Factor

Topics

• Active Transport, Cell Nucleus (genetics)
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Nucleus (genetics, metabolism, pathology)
• Epidermal Growth Factor (genetics, metabolism)
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Neoplasm Proteins (genetics, metabolism)
• Shc Signaling Adaptor Proteins (genetics, metabolism)
• beta Catenin (genetics, metabolism)