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.
Ding
Wei
W
Developmental Biology Program, Saban Research Institute Childrens Hospital Los Angeles, 4650 Sunset Boulevard, MS 35, Los Angeles, CA 90027, USA.
Warburton
David
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D015536:Down-Regulation; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D041701:Swiss 3T3 Cells; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases