Phospholipase A(2) proteins are major regulators of the arachidonic acid cascade and are involved in various cellular response I. Previously, we reported that group IB PLA(2), proteins stimulate MMP-2 activation and subsequent cell migration. Here, we describe a novel mechanism whereby sPLA(2)-induced proPMP-2 activation is regulated by intracellular cAMP in HT1080 cells, although sPLA(2) itself had no effect on the regulation of cAMP levels. Exogenous dibutyryl cAMP (a cAMP analogue) strongly inhibited proMMP-2 activation, and cAMP elevating agents, namely, cholera toxin (a Gs activator) and forskolin (an adenylyl cyclase activator), abrogated basal and sPLA(2)-induced proMMP-2 activation. We also found that the down-regulation of TIMP-2 expression and extracellular signal-regulated kinase (ERK)1/2 activation by sPLA2 were blocked by increasing the intracellular cAMP level. Taken together, our data indicate that sPLA(2)-induced proMMP-2 activation is influenced by intracellular cAMP levels via the modulations of TIMP-2 expression and ERK1/2 activation. (c) 2006 Elsevier Inc. All rights reserved.