Down-regulation of Sprouty2 via p38 MAPK plays a key role in the induction of cellular apoptosis by tumor necrosis factor-alpha.

Mammalian Sprouty2 (Spry2) is a key regulator of the receptor tyrosine kinase/ERK signaling pathway and involved in many biological processes, including cell growth, migration, and tumor suppression. Here, we demonstrated that the intracellular protein level of Spry2 was significantly down-regulated by tumor necrosis factor-alpha (TNF-alpha) in both murine Swiss 3T3 fibroblasts and MLE15 lung epithelial cells. Although TNF-alpha activates multiple signaling cascades, only the inhibitor of p38 MAPK pathway blocked TNF-alpha-induced Spry2 down-regulation. Moreover, since both the mRNA level and protein half-life of Spry2 were unaltered by TNF-alpha treatment, this indicated the possible involvement of a translational mechanism in mediating the inhibitory effect of TNF-alpha. Importantly, rescue of the TNF-alpha-induced down-regulation of Spry2 by gene overexpression led to reverse of the apoptotic effect of TNF-alpha in Swiss 3T3 cells. To our knowledge, this study is the first that reported the association of Spry2 with TNF-alpha signaling pathway.