Abstract
Simple SummaryThe epidermal growth factor receptor (EGFR) is activated through growth factor-dependent dimerization accompanied by functional reorganization of the actin cytoskeleton. Lee et al. demonstrate that CD99 activation by agonist ligands inhibits epidermal growth factor (EGF)-induced EGFR dimerization through impairment of cytoskeletal reorganization by protein tyrosine phosphatase non-receptor type 12 (PTPN12)-dependent c-Src/focal adhesion kinase (FAK) inactivation, thereby suppressing breast cancer growth.The epidermal growth factor receptor (EGFR), a member of ErbB receptor tyrosine kinase (RTK) family, is activated through growth factor-induced reorganization of the actin cytoskeleton and subsequent dimerization. We herein explored the molecular mechanism underlying the suppression of ligand-induced EGFR dimerization by CD99 agonists and its relevance to tumor growth in vivo. Epidermal growth factor (EGF) activated the formation of c-Src/focal adhesion kinase (FAK)-mediated intracellular complex and subsequently induced RhoA-and Rac1-mediated actin remodeling, resulting in EGFR dimerization and endocytosis. In contrast, CD99 agonist facilitated FAK dephosphorylation through the HRAS/ERK/PTPN12 signaling pathway, leading to inhibition of actin cytoskeletal reorganization via inactivation of the RhoA and Rac1 signaling pathways. Moreover, CD99 agonist significantly suppressed tumor growth in a BALB/c mouse model injected with MDA-MB-231 human breast cancer cells. Taken together, these results indicate that CD99-derived agonist ligand inhibits epidermal growth factor (EGF)-induced EGFR dimerization through impairment of cytoskeletal reorganization by PTPN12-dependent c-Src/FAK inactivation, thereby suppressing breast cancer growth.
Highlights
Many studies have focused on uncovering the molecular basis of epidermal growth factor receptor (EGFR) activation and its implication in tumor development and progression
Against focal adhesion kinase (FAK) or c-Src inhibited EGF-induced EGFR receptor–receptor interaction, endocytosis, as well as actin polymerization (Figure 1D–F and Figure S1D,E). These results suggest that c-Src/FAK-mediated actin cytoskeleton rearrangement plays an important role in ligand-induced EGFR dimerization and activation
After 10 min of treatment it showed the highest degree of interaction with EGFR (Figure 6C and Figure S5B). The interaction between both molecules in cells treated with EGF plus CD99CRIII3 occurred much earlier than that in cells treated with EGF only and was continued until 10 min after treatment. These results show that PTPN12 activated by CD99CRIII3 plays a critical role in the disruption of the intracellular adapter/kinase complex involved in the EGFR signaling cascade
Summary
Many studies have focused on uncovering the molecular basis of epidermal growth factor receptor (EGFR) activation and its implication in tumor development and progression. EGFR is activated by ligand binding, which induces sequentially their conformational change, auto- and trans-phosphorylation, dimerization, and internalization [1,2,3]. EGFR can be multimerized through a specific region of subdomain IV of the extracellular domain [4]. An increasing number of studies have suggested different aspects of EGFR activation. An inactive pre-formed dimer of EGFR without ligand was identified at the cell surface, which undergoes conformational changes during the activation process by stimulated ligand binding [5,6,7]. In spite of various aspects of the regulation of EGFR activation, dimerization of EGFR is a common feature required for its activation and transmission of downstream signals in tumorigenesis
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