Vaccinia H1-related phosphatase is a phosphatase of ErbB receptors and is down-regulated in non-small cell lung cancer.
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 of VHR inhibited the activation of phospholipase Cγ 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.
Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan 35053.
Jiz-Yuh
JY
Wang
Chi-Ling
CL
Yeh
Hsiao-Chin
HC
Chou
Chi-Hwa
CH
Yang
Yu-Ning
YN
Fu
Ya-Ting
YT
Chen
Hui-Wen
HW
Cheng
Chi-Ying F
CY
Huang
Hui-Ping
HP
Liu
Shiu-Feng
SF
Huang
Yi-Rong
YR
Chen
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D054640:Dual Specificity Phosphatase 3 / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous
C512478:EGFR protein, human; D066246:ErbB Receptors; C517025:DUSP3 protein, human; D054640:Dual Specificity Phosphatase 3; D051966:Phospholipase C gamma
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