Abstract
Expression of neuroendocrine-associated phosphatase (NEAP, also named as dual specificity phosphatase 26, [DUSP26]) is restricted to neuroendocrine tissues. We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells upon NGF stimulation. Conversely, suppressing NEAP expression by RNA interference enhanced TrkA and FGFR1 phosphorylation. NEAP was capable of de-phosphorylating TrkA and FGFR1 directly in vitro. NEAP-orthologous gene existed in zebrafish. Morpholino (MO) suppression of NEAP in zebrafish resulted in hyper-phosphorylation of TrkA and FGFR1 as well as abnormal body postures and small eyes. Differentiation of retina in zebrafishes with NEAP MO treatment was severely defective, so were cranial motor neurons. Taken together, our data indicated that NEAP/DUSP26 have a critical role in regulating TrkA and FGFR1 signaling as well as proper development of retina and neuronal system in zebrafish.
Highlights
Proteins of the nerve growth factor (NGF) family, known as neurotrophins (NTs), are evolutionary conserved factors with numerous functions
In this study we found that neuroendocrine-associated phosphatase (NEAP)/DUSP26 expression decreased TrkA and fibroblast growth factor receptor 1 (FGFR1) phosphorylation induced by NGF and, knockdown of NEAP enhanced TrkA and FGFR1 activation
We previously showed that NEAP down-regulated NGF-induced Akt activation without affecting other signaling pathways, such as ERK, JNK, and p38-MAPK
Summary
Proteins of the nerve growth factor (NGF) family, known as neurotrophins (NTs), are evolutionary conserved factors with numerous functions. NTs (including NGF, brain-derived growth factor [BDGF], NT3, and NT4/5) stimulate signals through receptor tyrosine kinases (RTKs, including TrkA, B, and C) and/or p75NTR, a tumor necrosis factor receptor family member. These two distinct classes of receptors are preferentially activated by mature NT and unprocessed pro-NT, respectively[1,2,3]. Due to the earlier identification, more information is known about the NGF-induced signaling and its biological effects mediated by TrkA and p75NTR1. NEAP/DUSP26 suppresses NGF-induced PC12 differentiation through down-regulating the phosphatidylinositide-3 kinase (PI3K)/Akt pathway and impairs PC12 cell growth through suppressing EGFR expressions by WT1-mediated transcriptional suppression[9, 11]. Our data supported a critical role of NEAP/DUSP26 in regulating RTK signaling in neuronal system
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