Abstract | OBJECTIVE: METHODS AND RESULTS: Because Src kinase family and Src homology region 2-domain phosphatase-2 (SHP-2) may regulate JNK activation, we studied the effect of shear stress on endothelial inflammation and JNK. Human umbilical vein endothelial cells preexposed to flow showed decreased tumor necrosis factor ( TNF)-alpha-induced c-Jun and NF-kappaB transcriptional activation. TNF-alpha-mediated JNK, c-Jun, and NF-kappaB activation required Src and SHP-2 activity. Shear stress significantly inhibited SHP-2 phosphatase activity without affecting TNF-alpha-induced Src family kinase activation. Because MEKK3 and Gab1 are critical for TNF-alpha-induced c-Jun and NF-kappaB activation, we determined the role of SHP-2 phosphatase activity in MEKK3 signaling. A catalytically inactive form of SHP-2 increased MEKK3/Gab1 interaction and inhibited MEKK3 (but not MEKK1)-mediated c-Jun and NF-kappaB activation. CONCLUSIONS: These results suggest that SHP-2 is a key mediator for the inhibitory effects of shear stress on TNF-alpha signaling in part via regulating MEKK3/Gab1 interaction, MEKK3 signaling, and subsequent adhesion molecule expression.
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Authors | Nicole Lerner-Marmarosh, Masanori Yoshizumi, Wenyi Che, James Surapisitchat, Hisaaki Kawakatsu, Masashi Akaike, Bo Ding, Qunhua Huang, Chen Yan, Bradford C Berk, Jun-ichi Abe |
Journal | Arteriosclerosis, thrombosis, and vascular biology
(Arterioscler Thromb Vasc Biol)
Vol. 23
Issue 10
Pg. 1775-81
(Oct 01 2003)
ISSN: 1524-4636 [Electronic] United States |
PMID | 12947019
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Adaptor Proteins, Signal Transducing
- GAB1 protein, human
- Intracellular Signaling Peptides and Proteins
- NF-kappa B
- Phosphoproteins
- Tumor Necrosis Factor-alpha
- JNK Mitogen-Activated Protein Kinases
- Mitogen-Activated Protein Kinases
- MAP Kinase Kinase Kinase 3
- MAP Kinase Kinase Kinases
- MAP3K3 protein, human
- Protein Phosphatase 2
- PTPN11 protein, human
- Protein Tyrosine Phosphatase, Non-Receptor Type 11
- Protein Tyrosine Phosphatases
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Topics |
- Adaptor Proteins, Signal Transducing
- Endothelium, Vascular
(cytology, metabolism)
- Hemorheology
- Humans
- Inflammation
- Intracellular Signaling Peptides and Proteins
- JNK Mitogen-Activated Protein Kinases
- MAP Kinase Kinase Kinase 3
- MAP Kinase Kinase Kinases
(metabolism)
- Mitogen-Activated Protein Kinases
(metabolism)
- NF-kappa B
(metabolism)
- Phosphoproteins
(metabolism)
- Protein Phosphatase 2
- Protein Tyrosine Phosphatase, Non-Receptor Type 11
- Protein Tyrosine Phosphatases
(metabolism)
- Transcriptional Activation
(drug effects)
- Tumor Necrosis Factor-alpha
(antagonists & inhibitors, pharmacology)
- Umbilical Cord
(cytology)
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