Effects of RING-SH2^(Grb2), a Chimeric Protein Containing the E3 Ligase Domain of Cbl, on the EGFR Pathway

Abstract

The E3 ubiquitin-protein ligase Casitas B-lineage lymphoma protein (Cbl) negatively regulates epidermal growth factor receptor (EGFR) signaling pathway in many organisms, and has crucial roles in cell growth, development and human pathologies, including lung cancers. RING-SH2Grb² a chimeric protein of 215 amino acids containing the RING domain of Cbl that provides E3 ligase activity, and the SH2 domain of Grb2 that serves as an adaptor for EGFR. In this study, we demonstrated that RING-SH2Grb² could promote the ubiquitinylation and degradation of EGFR in a human non-small cell lung carcinoma cell line H1299. Moreover, we discovered that the RING-SH2Grb² chimera promoted the internalization of ligand-bound EGFR, inhibited the growth of H1299 cells, and significantly suppressed tumor growth in a xenograft mouse model. In summary, our results revealed a potential new cancer therapeutic approach for non-small cell lung cancer.

Protein Engineering in the Ubiquitin System: Tools for Discovery and Beyond

“…6B). Indeed, the SH2 domain of growth factor receptor-binding domain 2 fused to either the RING domain of Cbl or U-box domain from carboxyl terminus of Hsc70-interacting protein (CHIP) is sufficient to downregulate EGFR in lung cancer cells (Lee et al, 2014;Zhong et al, 2015). Similarly, a SH2 domain fused to the U-box domain of CHIP downregulates breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog 1 kinase and inhibits tumor growth of chronic myeloid leukemia cells in mouse xenografts (Ru et al, 2016).…”