NEAP causes down-regulation of EGFR, subsequently induces the suppression of NGF-induced differentiation in PC12 cells.
Neuroendocrine-associated phosphatase (NEAP), an atypical dual specificity phosphatase is preferentially expressed in neuroendocrine cells. In this study we found that NEAP, but not NEAP-(C152S) mutant, evidently reduced epidermal growth factor (EGF) receptor (EGFR) downstream signaling, and impaired cell growth in response to EGF stimulation in PC12 cells. These phenomena were associated with NEAP-mediated down-regulation of EGFR mRNA and protein. NEAP had no significant effect on ErbB2/3 expression and phosphorylation levels in response to heregulin, indicating that the negative effect of NEAP on EGFR was selective. We showed that NEAP suppressed EGFR expression via decreasing the EGFR promoter activity and this was mediated through down-regulations of the Akt pathway and Wilms' tumor gene product (WT1). Consistent with these results, expression of WT1 reversed the suppressive effect of NEAP on EGFR promoter activity. Additionally, NEAP knockdown by RNA interference enhanced EGFR protein expression and nerve growth factor-induced differentiation, and an EGFR-specific inhibitor could reverse the later event. Taken together, our study indicated that NEAP modulates PC12 differentiation via suppression of EGFR expression and signaling.
Wang
Jiz-Yuh
JY
Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan Town, Taiwan.
Yang
Chi-Hwa
CH
Yeh
Chi-Ling
CL
Lin
Chia-Hua
CH
Chen
Yi-Rong
YR
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D009154:Mutation; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D025721:WT1 Proteins / Q000378:metabolism
D034741:RNA, Small Interfering; D025721:WT1 Proteins; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C483803:Egfr protein, rat; D066246:ErbB Receptors; D010744:Phosphoric Monoester Hydrolases