Activation of extracellular signal-regulated kinase by ultraviolet is mediated through Src-dependent epidermal growth factor receptor phosphorylation. Its implication in an anti-apoptotic function.
Ultraviolet (UV) irradiation stimulates stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), which is a member of the mitogen-activated protein kinase (MAPK) superfamily and implicated in stress-induced apoptosis. UV also induces the activation of another MAPK member, extracellular signal-regulated kinase (ERK), which is typically involved in a growth-signaling cascade. However, the UV-induced signaling pathway leading to ERK activation, together with the physiological role, has remained unknown. Here we examined the molecular mechanism and physiological function of UV-induced ERK activation in human epidermoid carcinoma A431 cells that retain a high number of epidermal growth factor (EGF) receptors. UV-induced ERK activation was accompanied with the Tyr phosphorylation of EGF receptors, and both responses were completely abolished in the presence of a selective EGF receptor inhibitor (AG1478) or the Src inhibitor PP2 and by the expression of a kinase-dead Src mutant. On the other hand, SAPK/JNK activation by UV was partially inhibited by these inhibitors. UV stimulated Src activity in a manner similar to the ERK activation, but the Src activation was insensitive to AG1478. UV-induced cell apoptosis measured by DNA fragmentation and caspase 3 activation was enhanced by AG1478 and an ERK kinase inhibitor (U0126) but inhibited by EGF receptor stimulation by the agonist. These results indicate that UV-induced ERK activation, which provides a survival signal against stress-induced apoptosis, is mediated through Src-dependent Tyr phosphorylation of EGF receptors.
Kitagawa
Daiju
D
Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
Tanemura
Shuhei
S
Ohata
Shinya
S
Shimizu
Nao
N
Seo
Jungwon
J
Nishitai
Gen
G
Watanabe
Tomomi
T
Nakagawa
Kentaro
K
Kishimoto
Hiroyuki
H
Wada
Teiji
T
Tezuka
Tohru
T
Yamamoto
Tadashi
T
Nishina
Hiroshi
H
Katada
Toshiaki
T
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004789:Enzyme Activation / Q000528:radiation effects; D066246:ErbB Receptors / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000528:radiation effects*; D010766:Phosphorylation; D014466:Ultraviolet Rays; D019061:src-Family Kinases / Q000502:physiology*
D066246:ErbB Receptors; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases