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337332 
Journal Article 
Lead acetate induces EGFR activation upstream of SFK and PKCa linkage to the Ras/Raf-1/ERK signaling 
Wang, CY; Wang, YT; Tzeng, DW; Yang, JL 
2009 
1 
Toxicology and Applied Pharmacology
ISSN: 0041-008X
EISSN: 1096-0333 
235 
2 
244-252 
English 
19133285 
WOS:000263994900012 
Lead acetate (Pb), a probable human carcinogen, can activate protein kinase C (PKC) upstream of extracellular signal-regulated kinase 1 and 2 (ERK1/2). Yet, it remains unclear whether Pb activation of PKC → ERK1/2 involves receptor/non-receptor tyrosine kinases and the Ras signaling transducer. Here we demonstrate a novel mechanism elicited by Pb for transmitting ERK1/2 signaling in CL3 human non-small-cell lung adenocarcinoma cells. Pb induction of higher steady-state levels of Ras-GTP was essential for increasing phospho-Raf-1[sub]S338[/sub] and phospho-ERKI/2. Pre-treatment of the cells with a conventional PKC inhibitor G66976 or depleting PKCa using specific small interfering RNA blocked Pb induction of Ras-GTP. Pb also activated cellular tyrosine kinases. Specific pharmacological inhibitors, PD153035 for epidermal growth factor receptor (EGFR) and SU6656 for Src family tyrosine kinases (SFK), but not AG1296 for platelet-derived growth factor receptor, could suppress the Pb-induced tyrosine kinases, PKCα, Ras-GTP, phospho-Raf-1[sub]S338[/sub] and phospho-ERKI/2. Furthermore, phosphorylation of tyrosines on the EGFR multiple autophosphorylation sites and the conserved SFK autophosphorylation site occurred during exposure of cells to Pb for 1-5 min and 5-30 min, respectively. Intriguingly, Pb activation of EGFR required the intrinsic kinase activity but not dimerization of the receptor. Inhibition of SFK or PKCα activities did not affect EGFR phosphorylation, while knockdown of EGFR blocked SFK phosphorylation and PKCa activation following Pb. Together, these results indicate that immediate activation of EGFR in response to Pb is obligatory for activation of SFK and PKCa and subsequent the Ras-Raf-1-MKK1/2-ERK1/2 signaling cascade. (English) 
Lead acetate; EGFR; Src; Autophosphorylation; PKCα; Ras/Raf-1/ERK; Toxicité; Carcinogène; Protein-tyrosine kinase; Transduction signal; Mitogen-activated protein kinase; Extracellular signal-regulated protein kinase; Gène ras; Gène onc cellulaire; Protooncogène; Liaison génétique; Récepteur facteur croissance épiderme; Plomb; Acétate; Métal lourd; Transferases; Enzyme; Gène src; Gène raf1; Toxicity; Carcinogen; Signal transduction; Ras gene; C-Onc gene; Protooncogene; Genetic linkage; Epidermal growth factor receptor; Lead; Acetate; Heavy metal; Toxicidad; Carcinógeno; Autofosforilación; Transducción señal; Gen ras; Gen onc celular; Protooncogen; Ligamiento genético; Receptor del factor de crecimiento epidérmico; Plomo; Acetato; Metal pesado; Enzima