Activation of Extracellular Signal-regulated Kinase by Ultraviolet Is Mediated through Src-dependent Epidermal Growth Factor Receptor Phosphorylation

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.

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

“…These effects are significantly inhibited by suppression of K + channel activity using 4-AP (1 mM), suggesting that K + channel activity is required for UV irradiation-induced activation of the ERK cascade. The functional significance of UV irradiation moderately and stably activating the ERK limb may be explained by a previous study demonstrating that the ERK limb activation by UV irradiation promotes cell survival in A431 cells (Kitagawa et al, 2002). Relative to JNK/SAPK activation, there is also a much weaker activation of p38 in corneal epithelial cells in response to UV irradiation.…”

Cisplatin-induced activation of the EGF receptor

“…Src-family kinases play a role in the cellular response to stress agents, such as UV light, heat shock and oxidative stress (Aikawa et al, 1997;Lin et al, 1997;Yoshizumi et al, 2000). Furthermore, Src is implicated in cross-communication among different signaling systems, such as EGFR activation by integrins (Moro et al, 2002), EGFR cross talk with Na + /K + -ATPase (Haas et al, 2002) or EGFR activation induced by heterotrimeric G proteins (Luttrell et al, 1997;Maudsley et al, 2000), hydrogen peroxide (Chen et al, 2001), UV irradiation (Kitagawa et al, 2001), and Zn 2+ ions (Wu et al, 2002).…”

“…Pp60 Src cooperates with the EGFR in several signaling settings (Parsons and Parsons, 1997) and is involved in the activation of MAP kinases in response to UV radiation and oxidative stress (Aikawa et al, 1997;Kitagawa et al, 2001). To examine if Src-family kinases are involved in CDDP-induced EGFR activation, we employed PP1, an inhibitor of Src-family kinases (Hanke et al, 1996).…”

The Src Family Kinase Yes Triggers Hyperosmotic Activation of the Epidermal Growth Factor Receptor and CD95

“…Multiple receptor pathways can couple with Src kinases, but Src family kinases are also activated in response to several forms of cell stress (for review see Refs. 13 and 14), such as UV radiation (29), hydrogen peroxide (30,31), or anisoosmolarity (11,12,32). c-Src was implicated in both hepatocellular volume increase and decrease in response to hyper-or hypoosmolarity, respectively (8,32).…”