title: 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.
abstract: 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.
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Kitagawa
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tanemura
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohata
authors.forename: Nao
authors.initials: N
authors.lastname: Shimizu
authors.forename: Jungwon
authors.initials: J
authors.lastname: Seo
authors.forename: Gen
authors.initials: G
authors.lastname: Nishitai
authors.forename: Tomomi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Teiji
authors.initials: T
authors.lastname: Wada
authors.forename: Tohru
authors.initials: T
authors.lastname: Tezuka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Katada
mesh_terms: 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*
chemical_list: D066246:ErbB Receptors; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases