Epidermal growth factor receptor is modulated by redox through multiple mechanisms -: Effects of reductants and H2O2

被引:67
作者
Kamata, H [1 ]
Shibukawa, Y [1 ]
Oka, SI [1 ]
Hirata, H [1 ]
机构
[1] Himeji Inst Technol, Fac Sci, Dept Life Sci, Hyogo 6781297, Japan
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 2000年 / 267卷 / 07期
关键词
epidermal growth factor receptor; H2O2; N-acetyl-L-cysteine; redox;
D O I
10.1046/j.1432-1327.2000.01194.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The cellular redox state has been shown to play an essential role in cellular signaling systems. Here we investigate the effects of reductants and H2O2 on the signaling of epidermal growth factor (EGF) in cells. H2O2 induced the phosphorylation of the EGF receptor and the formation of a receptor complex comprising Shc, Grb2, Sos, and the EGF receptor. Dimerization or oligomerization of the EGF receptor was not induced by H2O2. Protein tyrosine phosphatase (PTP) assay showed that H2O2 suppressed dephosphorylation of the EGF receptor in cell lysates, suggesting that inactivation of PTP was involved in H2O2-induced activation of the EGF receptor. In contrast, the reductants N-acetyl-L-cysteine [Cys(Ac)] and dithiothreitol markedly suppressed EGF-induced dimerization and activation of the EGF receptor in cells. In accordance with suppression of the EGF receptor, Cys(Ac) suppressed EGF-induced activation of Ras, phosphatidylinositol 3-kinase and mitogen-activated protein kinase. Dithiothreitol completely inhibited EGF binding and kinase activation of the EGF receptor both in vitro and in vivo. In contrast, Cys(Ac) suppressed high-affinity EGF-binding sites on the cells, but had no effect on low-affinity binding sites. Furthermore, Cys(Ac) did not suppress EGF-induced kinase activation or dimerization of the EGF receptor in vitro, indicating that it suppressed the EGF receptor through a redox-sensitive cellular process or processes. Thus, the EGF receptor is regulated by redox through multiple steps including dephosphorylation by PTP, ligand binding, and a Cys(Ac)-sensitive cellular process or processes.
引用
收藏
页码:1933 / 1944
页数:12
相关论文
共 64 条
[1]   REDOX REGULATION OF FOS AND JUN DNA-BINDING ACTIVITY INVITRO [J].
ABATE, C ;
PATEL, L ;
RAUSCHER, FJ ;
CURRAN, T .
SCIENCE, 1990, 249 (4973) :1157-1161
[2]   Disulfide bond structure of human epidermal growth factor receptor [J].
Abe, Y ;
Odaka, M ;
Inagaki, F ;
Lax, I ;
Schlessinger, J ;
Kohda, D .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (18) :11150-11157
[3]   UV IRRADIATION AND HEAT-SHOCK MEDIATE JNK ACTIVATION VIA ALTERNATE PATHWAYS [J].
ADLER, V ;
SCHAFFER, A ;
KIM, J ;
DOLAN, L ;
RONAI, Z .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (44) :26071-26077
[4]   Oxidative stress activates extracellular signal-regulated kinases through Src and ras in cultured cardiac myocytes of neonatal rats [J].
Aikawa, R ;
Komuro, I ;
Yamazaki, T ;
Zou, YZ ;
Kudoh, S ;
Tanaka, M ;
Shiojima, I ;
Hiroi, Y ;
Yazaki, Y .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (07) :1813-1821
[5]  
ANDERSON ME, 1985, METHOD ENZYMOL, V113, P548
[6]   Epidermal growth factor (EGF)-induced generation of hydrogen peroxide - Role in EGF receptor-mediated tyrosine phosphorylation [J].
Bae, YS ;
Kang, SW ;
Seo, MS ;
Baines, IC ;
Tekle, E ;
Chock, PB ;
Rhee, SG .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (01) :217-221
[7]   REDOX REGULATION OF A PROTEIN TYROSINE KINASE IN THE ENDOPLASMIC-RETICULUM [J].
BAUSKIN, AR ;
ALKALAY, I ;
BEN-NERIAH, Y .
CELL, 1991, 66 (04) :685-696
[8]   MECHANISM OF EPIDERMAL GROWTH-FACTOR RECEPTOR AUTOPHOSPHORYLATION AND HIGH-AFFINITY BINDING [J].
BONISCHNETZLER, M ;
PILCH, PF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (22) :7832-7836
[9]   PARALLEL SIGNAL-PROCESSING AMONG MAMMALIAN MAPKS [J].
CANO, E ;
MAHADEVAN, LC .
TRENDS IN BIOCHEMICAL SCIENCES, 1995, 20 (03) :117-122
[10]   PARTICIPATION OF REACTIVE OXYGEN SPECIES IN THE LYSOPHOSPHATIDIC ACID-STIMULATED MITOGEN-ACTIVATED PROTEIN-KINASE KINASE ACTIVATION PATHWAY [J].
CHEN, QL ;
OLASHAW, N ;
WU, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (48) :28499-28502