Src tyrosine kinase inhibitor PP2 suppresses ERK1/2 activation and epidermal growth factor receptor transactivation by X-irradiation.
Exposure of MDA-MB-468 cells to ionizing radiation (IR) caused biphasic activation of ERK as indicated by its phosphorylation at Thr202/Tyr204. Specific epidermal growth factor receptor (EGFR) inhibitor AG1478 and specific Src inhibitor PP2 inhibited IR-induced ERK1/2 activation but phosphatidylinositol-3 kinase inhibitor wortmannin did not. IR caused EGFR tyrosine phosphorylation, whereas it did not induce EGFR autophosphorylation at Tyr992, Tyr1045, and Tyr1068 or Src-dependent EGFR phosphorylation at Tyr845. SHP-2, which positively regulates EGFR/Ras/ERK signaling cascade, became activated by IR as indicated by its phosphorylation at Tyr542. This activation was inhibited by PP2 not by AG1478, which suggests Src-dependent activation of SHP-2. Src and PTPalpha, which positively regulates Src, became activated as indicated by phosphorylation at Tyr416 and Tyr789, respectively. These data suggest that IR-induced ERK1/2 activation involves EGFR through a Src-dependent pathway that is distinct from EGFR ligand activation.
Li
Zhiping
Z
Department of Radiation Research, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Hosoi
Yoshio
Y
Cai
Keshong
K
Tanno
Yuji
Y
Matsumoto
Yoshihisa
Y
Enomoto
Atsushi
A
Morita
Akinori
A
Nakagawa
Keiichi
K
Miyagawa
Kiyoshi
K
D000730:Androstadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007259:Infrared Rays; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011799:Quinazolines; D011839:Radiation, Ionizing; D015398:Signal Transduction; D013696:Temperature; D013997:Time Factors; D015533:Transcriptional Activation; D014443:Tyrosine / Q000737:chemistry; D020032:Tyrphostins / Q000494:pharmacology; D000077191:Wortmannin; D014965:X-Rays; D019061:src-Family Kinases / Q000378:metabolism*
C412373:AG 1879; D000730:Androstadienes; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D011743:Pyrimidines; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D014443:Tyrosine; D004815:Epidermal Growth Factor; D006160:Guanosine Triphosphate; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D000077191:Wortmannin