期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 12, 页码 10177-10184出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.163295
关键词
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资金
- National Health Research Institutes [MG-098-PP-03, MG-099-PP-03]
- Department of Health [DOH98-TD-G-111-026]
- Taiwan National Science Council [97-2320-B-400-008-MY3]
Vaccinia H1-related phosphatase (VHR) is classified as a dual specificity phosphatase. Unlike typical dual specificity phosphatases, VHR lacks the MAPK-binding domain and shows poor activity against MAPKs. We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression ofVHRinhibited the activation of phospholipase C gamma and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. Decreasing VHR expression by RNA interference caused higher EGFR phosphorylation at Tyr-992. In addition to EGFR, VHR also directly dephosphorylated ErbB2. Consistent with these results, suppression of VHR augmented the foci formation ability of H1299 non-small cell lung cancer (NSCLC) cells, whereas overexpression of VHR suppressed cell growth in both two- and three-dimensional cultures. Expression of VHR also suppressed tumor formation in a mouse xenograft model. Furthermore, VHR expression was significantly lower in NSCLC tissues in comparison to that in normal lung tissues. Collectively, this study shows that down- regulation of VHR expression enhances the signaling of ErbB receptors and may be involved in NSCLC pathogenesis.
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