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

SUBMITTER: Liu L

PROVIDER: S-EPMC6355651 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Liu Lei L Yang Yi Y Liu Shihua S Tao Tianyu T Cai Junchao J Wu Jueheng J Guan Hongyu H Zhu Xun X He Zhenjian Z Li Jun J Song Erwei E Zeng Musheng M Li Mengfeng M

Oncogene 20180903 5

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-c ...[more]

PMID: 30177836

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Project description:BackgroundAdherent junction associated protein 1 (AJAP1), a typical molecule of adherent junctions, has been found to be a tumor suppressor in many cancer types. Aberrant activation of β-catenin has been demonstrated to be associated with malignant biological properties of tumors including breast cancer. This study aimed to investigate the function and mechanism of AJAP1-mediated β-catenin activity of breast cancer lines in vitro and in breast cancer patients.MethodsAJAP1 and β-catenin expressions in breast cancer tissues and cell lines were detected by immunohistochemistry, western blotting and qRT-PCR. The EGF/EGFR axis-mediated AJAP1 attenuated β-catenin nuclear location was measured by western blotting, immunofluorescence assay, co-immunoprecipitation, luciferase assay and ubiquitination assays. Furthermore, the function of AJAP1 and β-catenin regulated breast cancer progression was explored both in vivo and in vitro.ResultsIt was found that AJAP1 had a high negative correlation with β-catenin nuclear expression and was a novel tumor suppressor in breast cancer. AJAP1 loss can mediate β-catenin accumulated in cytoplasm and then transferred it to the nucleus, activating β-catenin transcriptional activity and downstream genes. Additionally, β-catenin can reverse the invasion, proliferation ability and tumorigenicity of the depletion of AJAP1 caused both in vivo and in vitro. Besides, EGF/EGFR also involved in the process of AJAP1-depiction induced β-catenin transactivation to the nucleus. More importantly, EGFR depletion/AJAP1 knocked down promoted the progression of breast cancer by regulating the activity of β-catenin nuclear transactivation.ConclusionThis study demonstrated that AJAP1 acted as a putative tumor suppressor while β-catenin nuclear localization positively fed back on EGF/EGFR-attenuated AJAP1 expression in breast cancer, which might be beneficial to develop new therapeutic targets for decreasing nuclear β-catenin-mediated malignancy in breast cancer.

Dataset Information

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

Publications

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

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