SHP-2-Erk signaling regulates concanavalin A-dependent production of TIMP-2.
To search for the signaling critical for the production of tissue inhibitor of metalloproteinase-2 (TIMP-2), we investigated the role of SHP-2 in TIMP-2 production with Concanavalin A (Con A)-treated cells. In wild-type fibroblasts, Con A-treatment dramatically activated TIMP-2 production. In contrast, production of TIMP-2 in response to Con A-treatment was severely impaired in cells expressing mutant SHP-2 whose 65 amino acids in the SH2-N domain were deleted. Con A-treatment activated dual signaling pathways, Erk and p38, in a SHP-2-dependent manner. Pretreatment of wild-type cells with U0126, a potent inhibitor of MEK1, significantly inhibited the production of TIMP-2, whereas SB203580, a specific inhibitor for p38, could not. Finally, expression of exogenous wild-type SHP-2 in SHP-2 mutant cells clearly rescued Erk activation and TIMP-2 production in response to Con A-treatment. Taken together, our results strongly suggest that SHP-2 plays a critical role as a positive modulator for the production of TIMP-2 via MEK1-Erk signaling in fibroblasts.
Biswas
Md Helal Uddin
MH
Department of Cancer Biology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Hasegawa
Hitoki Hitoki
HH
Rahman
M Aminur
MA
Huang
Pengyu
P
Mon
Naing Naing
NN
Ruhul Amin
A R M
AR
Senga
Takeshi
T
Kannagi
Reiji
R
Hamaguchi
Michinari
M
D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005347:Fibroblasts / Q000201:enzymology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis*
D047908:Intracellular Signaling Peptides and Proteins; D003208:Concanavalin A; D019716:Tissue Inhibitor of Metalloproteinase-2; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases