Vaccinia H1-related phosphatase (VHR) is classified as a dual-specificity phosphatase (DUSP). Unlike typical DUSPs, VHR lacks mitogen-activated protein kinase (MAPK)-binding domain, and shows poor activity against MAPKs. We found that epidermal growth factor receptor (EGFR) was a direct substrate of VHR, and that overexpression of VHR down-regulated EGFR phosphorylation, particularly at tyrosine (Tyr) 992 residue. Expression of VHR inhibited the activation of phospholipase Cgamma and protein kinase C, both downstream effectors of EGFR's Tyr 992 phosphorylation. 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, while overexpression of VHR suppressed cell growth in both two- and three-dimension 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.
Date:
2011-03
Relation:
Journal of Biological Chemistry. 2011 Mar;286(12):10177-10184.
