cAMP elevating agents suppress secretory phospholipase A(2)-induced matrix metalloproteinase-2 activation.
Phospholipase A2 proteins are major regulators of the arachidonic acid cascade and are involved in various cellular responses. Previously, we reported that group IB PLA2 proteins stimulate MMP-2 activation and subsequent cell migration. Here, we describe a novel mechanism whereby sPLA2-induced proMMP-2 activation is regulated by intracellular cAMP in HT1080 cells, although sPLA2 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 sPLA2-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 sPLA2-induced proMMP-2 activation is influenced by intracellular cAMP levels via the modulations of TIMP-2 expression and ERK1/2 activation.
Lee
Chuhee
C
Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu 705-035, South Korea; Aging-Associated Vascular Disease Research Center, Daegu 705-035, South Korea.
Lee
Jingu
J
Choi
Young-Ae
YA
Kang
Shin-Sung
SS
Baek
Suk-Hwan
SH
D002460:Cell Line; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism*; D004789:Enzyme Activation; D005354:Fibrosarcoma / Q000378:metabolism*; D054501:Group II Phospholipases A2; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D000242:Cyclic AMP; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D020778:Matrix Metalloproteinase 2