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HER3 intracellular domains play a crucial role in HER3/HER2 dimerization and activation of downstream signaling pathways

HER3 intracellular domains play a crucial role in HER3/HER2 dimerization and activation of downstream signaling pathways

作     者:Byung-Kwon Choi Xiumei Cai Bin Yuan Zhao Huang Xuejun Fan Hui Deng Ningyan Zhang Zhiqiang An 

作者机构:Texas Therapeutics InstituteBrown Foundation Institute of Molecular MedicineUniversity of Texas Health Science Center at HoustonHoustonTX 77030USA Department of Biochemistry and Molecular BiologyShanghai Medical CollegeFudan UniversityShanghai 200032China The Methodist Hospital Research InstituteHoustonTX 77030USA 

出 版 物:《Protein & Cell》 (蛋白质与细胞(英文版))

年 卷 期:2012年第3卷第10期

页      面:781-789页

核心收录:

学科分类:1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基  金:partially funded by grants from the Texas Emerging Technology Fund and the Welch Foundation 

主  题:HER3 HER2 cell proliferation cell migration PI3K/AKT MAPK/ERK1/2 

摘      要:Dimerization among the EGFR family of tyrosine kinase receptors leads to allosteric activation of the kinase domains of the *** other members in the family,the kinase domain of HER3 lacks key amino acid residues for catalytic *** a result,HER3 is suggested to serve as an allosteric activator of other EGFR family members which include EGFR,HER2 and *** study the role of intracellular domains in HER3 dimerization and activation of downstream signaling pathways,we constructed HER3/HER2 chimeric receptors by replacing the HER3 kinase domain(HER3-2-3)or both the kinase domain and the C-terminal tail(HER3-2-2)with the HER2 counterparts and expressed the chimeric receptors in Chinese hamster ovary(CHO)*** over expression of the intact human HER3 transformed CHO cells with oncogenic properties such as AKT/ERK activation and increased proliferation and migration,CHO cells expressing the HER3-2-3 chimeric receptor showed significantly reduced HER3/HER2 dimerization and decreased phosphorylation of both AKT and ERK1/2 in the presence of neuregulin-1(NRG-1).In contrast,CHO cells expressing the HER3-2-2 chimeric receptor resulted in a total loss of downstream AKT activation in response to NRG-1,but maintained partial activation of ERK1/*** results demonstrate that the intracellular domains play a crucial role in HER3’s function as an allosteric activator and its role in downstream signaling.

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