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J. Biol. Chem., Vol. 282, Issue 34, 24720-24730, August 24, 2007

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G Protein Subunits Augment UVB-induced Apoptosis by Stimulating the Release of Soluble Heparin-binding Epidermal Growth Factor from Human Keratinocytes^*

MiRan Seo, Mi-Jeong Lee, Jin Hee Heo, Yun-Il Lee, Yeni Kim, So-Young Kim, Eun-So Lee, and Yong-Sung Juhnn¹

From the Department of Biochemistry and Molecular Biology and Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-779 and the Department of Dermatology, Ajou University School of Medicine, Suwon 443-749, Korea

UV radiation induces various cellular responses by regulating the activity of many UV-responsive enzymes, including MAPKs. The subunit of the heterotrimeric GTP-binding protein (G) was found to mediate UV-induced p38 activation via epidermal growth factor receptor (EGFR). However, it is not known how G mediates the UVB-induced activation of EGFR, and thus we undertook this study to elucidate the mechanism. Treatment of HaCaT-immortalized human keratinocytes with conditioned medium obtained from UVB-irradiated cells induced the phosphorylations of EGFR, p38, and ERK but not that of JNK. Blockade of heparin-binding EGF-like growth factor (HB-EGF) by neutralizing antibody or CRM197 toxin inhibited the UVB-induced activations of EGFR, p38, and ERK in normal human epidermal keratinocytes and in HaCaT cells. Treatment with HB-EGF also activated EGFR, p38, and ERK. UVB radiation stimulated the processing of pro-HB-EGF and increased the secretion of soluble HB-EGF in medium, which was quantified by immunoblotting and protein staining. In addition, treatment with CRM179 toxin blocked UV-induced apoptosis, but HB-EGF augmented this apoptosis. Moreover, UVB-induced apoptosis was reduced by inhibiting EGFR or p38. The overexpression of G₁₂ increased EGFR-activating activity and soluble HB-EGF content in conditioned medium, but the sequestration of G by the carboxyl terminus of G protein-coupled receptor kinase 2 (GRK2ct) produced the opposite effect. The activation of Src increased UVB-induced, G-mediated HB-EGF secretion, but the inhibition of Src blocked that. Overexpression of G increased UVB-induced apoptosis, and the overexpression of GRK2ct decreased this apoptosis. We conclude that G mediates UVB-induced human keratinocyte apoptosis by augmenting the ectodomain shedding of HB-EGF, which sequentially activates EGFR and p38.

Received for publication, March 19, 2007 , and in revised form, May 16, 2007.

^* This work was supported by Seoul National University Hospital Research Fund Grant 03-03-2004-017-0, by a research grant from the Cancer Research Institute, Seoul National University (2004), by the 2007 BK21 Project for Medicine, and by the Korea Research Foundation Grant KRF-2006-353-E00006 funded by Korea Government (MOEHRD). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul 110-799, Republic of Korea. Tel.: 82-2-740-8247; Fax: 82-2-744-4534; E-mail: juhnn{at}snu.ac.kr.

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