PTEN suppression promotes neurite development exclusively in differentiating PC12 cells via PI3-kinase and MAP kinase signaling.
As a dual-specificity phosphatase catalyzing the dephosphorylation of phosphatidylinositols and protein substrates, PTEN is critically involved in the nervous system development. However, the regulatory role of PTEN in neurite outgrowth is still controversial, and the downstream signaling events remain elusive. Here, we show that PTEN knockdown promoted the proliferation and survival but not the neurite outgrowth of rat pheochromocytoma PC12 cells when exposed to nerve growth factor (NGF). In contrast, selective PTEN silencing in differentiating PC12 cells that express nestin significantly facilitated neurite elongation. Elevated Akt and Erk1/2 phosphorylation was involved in accelerated NGF-induced neurite development of PC12 cells following PTEN knockdown. Discriminated roles of the lipid phosphatase and protein phosphatase activities of PTEN in neurite development, as well as the detailed molecular profiles affected by these phosphatase activities, were defined by restored expression of a lipid phosphatase-deficient PTEN mutant following endogenous PTEN silencing in PC12 cells. Our study suggests an overall inhibitory effect of PTEN in neurite development reconciled by a probably indispensable role of this phosphatase in the initiation of PC12 cell differentiation.
Jia
Lintao
L
Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an 710032, China. jialth@fmmu.edu.cn
Ji
Shaoping
S
Maillet
Jean-Christian
JC
Zhang
Xia
X
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D016501:Neurites / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016716:PC12 Cells; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat