Activation of the EGF receptor signaling pathway in human airway epithelial cells exposed to metals

被引:154
作者
Wu, WD
Graves, LM
Jaspers, I
Devlin, RB
Reed, W
Samet, JM
机构
[1] Univ N Carolina, Ctr Environm Med & Lung Biol, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA
[3] US EPA, Natl Hlth Effects & Environm Res Lab, Human Studies Div, Res Triangle Pk, NC 27711 USA
关键词
signal transduction; air pollution; epidermal growth factor receptor; mitogen-activated protein kinase kinase;
D O I
10.1152/ajplung.1999.277.5.L924
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
We have previously shown that exposure to combustion-derived metals rapidly (within 20 min) activated mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK), in the human bronchial epithelial cell line BEAS. To study the mechanisms responsible for metal-induced activation of ERK, we examined the effect of noncytotoxic exposures to As, Cu, V, or Zn on the kinases upstream of ERK in the epidermal growth factor (EGF) receptor signaling pathway. Western blotting using phospho-specific ERK1/2 antibody demonstrated the selective MEK1/2 inhibitor PD-98059 blocked metal-induced phosphorylation of ERK1/2. Meanwhile, Western blotting using a phospho-specific MEK1/2 antibody showed that these metals induce a rapid phosphorylation of MEK1/2. Kinase activity assays confirmed the activation of MEK1/2 by metal treatment. Immunoprecipitation studies demonstrated that As, Cu, V, or Zn induces EGF receptor phosphorylation. Furthermore, the EGF receptor-specific tyrosine kinase inhibitor (PD-153035) significantly blocked the phosphorylation of MEK1/2 initiated by metals. Interestingly, we observed low levels of Raf-l activity that were not increased by metal exposure in these cells through kinase activity assay. Finally, transfection assays showed that MEK1/2 inhibition could inhibit traits-activation of Elk1, a transcription factor in the ERK pathway, in BEAS cells exposed to metals. Together, these data demonstrate that As, Cu, V, and Zn can activate the EGF receptor signaling pathway in BEAS cells and suggest that this mechanism may be involved in pulmonary responses to metal inhalation.
引用
收藏
页码:L924 / L931
页数:8
相关论文
共 60 条
[1]   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
[2]  
AHN NG, 1992, CIBA F SYMP, V164, P113
[3]   PD-098059 IS A SPECIFIC INHIBITOR OF THE ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASE KINASE IN-VITRO AND IN-VIVO [J].
ALESSI, DR ;
CUENDA, A ;
COHEN, P ;
DUDLEY, DT ;
SALTIEL, AR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (46) :27489-27494
[4]   The CCAAT-binding proteins CP1 and NF-I cooperate with ATF-2 in the transcription of the fibronectin gene [J].
Alonso, CR ;
Pesce, CG ;
Kornblihtt, AR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (36) :22271-22279
[5]   The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis in response to tumour necrosis factor [J].
Beyaert, R ;
Cuenda, A ;
VandenBerghe, W ;
Plaisance, S ;
Lee, JC ;
Haegeman, G ;
Cohen, P ;
Fiers, W .
EMBO JOURNAL, 1996, 15 (08) :1914-1923
[6]   Molecular cloning of mitogen-activated protein ERK kinase kinases (MEKK) 2 and 3 - Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase [J].
Blank, JL ;
Gerwins, P ;
Elliott, EM ;
Sather, S ;
Johnson, GL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (10) :5361-5368
[7]   SPECTROSCOPIC CHARACTERIZATION OF THIOREDOXIN COVALENTLY MODIFIED WITH MONOFUNCTIONAL ORGANOARSENICAL REAGENTS [J].
BROWN, SB ;
TURNER, RJ ;
ROCHE, RS ;
STEVENSON, KJ .
BIOCHEMISTRY, 1987, 26 (03) :863-871
[8]   RECEPTOR TYROSINE KINASES [J].
CADENA, DL ;
GILL, GN .
FASEB JOURNAL, 1992, 6 (06) :2332-2337
[9]  
CAMPBELL JS, 1995, RECENT PROG HORM RES, V50, P131
[10]   PARALLEL SIGNAL-PROCESSING AMONG MAMMALIAN MAPKS [J].
CANO, E ;
MAHADEVAN, LC .
TRENDS IN BIOCHEMICAL SCIENCES, 1995, 20 (03) :117-122