期刊
CANCERS
卷 12, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/cancers12102895
关键词
actin cytoskeletal reorganization; breast cancer; CD99 agonist; EGFR dimerization; endocytosis; FAK dephosphorylation; PTPN12; Rac1; RhoA; tripeptide
类别
资金
- Basic science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2018R1D1A3B07043170]
- Kangwon National University [520170543]
- National Research Foundation of Korea [2018R1D1A3B07043170] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Simple Summary The 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.
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