Ultraviolet (UV) radiation induces cyclooxygenase-2 expression to produce cellular responses including aging and carcinogenesis in skin. We hypothesised that heterotrimeric G proteins mediate UV-induced COX-2 expression by stimulating secretion of soluble HB-EGF (sHB-EGF). In this study, we aimed to elucidate the role and underlying mechanism of the a subunit of Gq protein (G alpha q) in UVB-induced HB-EGF secretion and COX-2 induction. We found that expression of constitutively active G alpha q (G alpha qQL) augmented UVB-induced HB-EGF secretion. which was abolished by knockdown of G alpha q with shRNA in HaCaT human keratinocytes. G alpha q was found to mediate the UVB-induced HB-EGF secretion by sequential activation of phospholipase C (PLC), protein kinase C delta (PKC delta), and matrix metaloprotease-2 (MMP-2). Moreover, G alpha qQL mediated UVB-induced COX-2 expression in an HH-EGF-, EGFR-, and p38-dependent manner. From these results, we concluded that G alpha q mediates UV-induced COX-2 expression through activation of EGFR by HB-EGF, of which ectodomain shedding was stimulated through sequential activation of PLC, PKC delta and MMP-2 in HaCaT cells. (C) 2010 Elsevier Inc. All rights reserved.