SHP-2 Promotes the Maturation of Oligodendrocyte Precursor Cells Through Akt and ERK1/2 Signaling In Vitro
MetadataShow full item record
AbstractBackground: Oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes (OLs), which are responsible for myelination. Myelin is essential for saltatory nerve conduction in the vertebrate nervous system. However, the molecular mechanisms of maturation and myelination by oligodendrocytes remain elusive.
Methods and Findings: In the present study, we showed that maturation of oligodendrocytes was attenuated by sodium orthovanadate (a comprehensive inhibitor of tyrosine phosphatases) and PTPi IV (a specific inhibitor of SHP-2). It is also found that SHP-2 was persistently expressed during maturation process of OPCs. Down-regulation of endogenous SHP-2 led to impairment of oligodendrocytes maturation and this effect was triiodo-L-thyronine (T3) dependent. Furthermore, over-expression of SHP-2 was shown to promote maturation of oligodendrocytes. Finally, it has been identified that SHP-2 was involved in activation of Akt and extracellular-regulated kinases 1 and 2 (ERK1/2) induced by T3 in oligodendrocytes.
Conclusions: SHP-2 promotes oligodendrocytes maturation via Akt and ERK1/2 signaling in vitro.
CitationPLoS One. 2011 Jun 20; 6(6):e21058
- The extracellular matrix glycoprotein Tenascin-C is expressed by oligodendrocyte precursor cells and required for the regulation of maturation rate, survival and responsiveness to platelet-derived growth factor.
- Authors: Garwood J, Garcion E, Dobbertin A, Heck N, Calco V, ffrench-Constant C, Faissner A
- Issue date: 2004 Nov
- Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo.
- Authors: Mannell H, Hellwig N, Gloe T, Plank C, Sohn HY, Groesser L, Walzog B, Pohl U, Krotz F
- Issue date: 2008
- Sustained activation of ERK1/2 MAPK in oligodendrocytes and schwann cells enhances myelin growth and stimulates oligodendrocyte progenitor expansion.
- Authors: Ishii A, Furusho M, Bansal R
- Issue date: 2013 Jan 2
- Diosgenin promotes oligodendrocyte progenitor cell differentiation through estrogen receptor-mediated ERK1/2 activation to accelerate remyelination.
- Authors: Xiao L, Guo D, Hu C, Shen W, Shan L, Li C, Liu X, Yang W, Zhang W, He C
- Issue date: 2012 Jul
- Muscarinic acetylcholine receptors mediate oligodendrocyte progenitor survival through Src-like tyrosine kinases and PI3K/Akt pathways.
- Authors: Cui QL, Fogle E, Almazan G
- Issue date: 2006 Apr
Showing items related by title, author, creator and subject.
Novel Somatic Mutations to PI3K Pathway Genes in Metastatic MelanomaShull, Austin Y.; Latham-Schwark, Alicia; Ramasamy, Poornema; Leskoske, Kristin; Oroian, Dora; Birtwistle, Marc R.; Buckhaults, Phillip J.; GHSU Cancer Center (2012-08-17)Background: BRAFV600 inhibitors have offered a new gateway for better treatment of metastatic melanoma. However, the overall efficacy of BRAFV600 inhibitors has been lower than expected in clinical trials, and many patients have shown resistance to the drugâ s effect. We hypothesized that somatic mutations in the Phosphoinositide 3-Kinase (PI3K) pathway, which promotes proliferation and survival, may coincide with BRAFV600 mutations and contribute to chemotherapeutic resistance.
Linear Approaches to Intramolecular Forster Resonance Energy Transfer Probe Measurements for Quantitative ModelingBirtwistle, Marc R.; von Kriegsheim, Alexander; Kida, Katarzyna; Schwarz, Juliane P.; Anderson, Kurt I.; Kolch, Walter; GHSU Cancer Center (2011-11-16)Numerous unimolecular, genetically-encoded Forster Resonance Energy Transfer (FRET) probes for monitoring biochemical activities in live cells have been developed over the past decade. As these probes allow for collection of high frequency, spatially resolved data on signaling events in live cells and tissues, they are an attractive technology for obtaining data to develop quantitative, mathematical models of spatiotemporal signaling dynamics. However, to be useful for such purposes the observed FRET from such probes should be related to a biological quantity of interest through a defined mathematical relationship, which is straightforward when this relationship is linear, and can be difficult otherwise. First, we show that only in rare circumstances is the observed FRET linearly proportional to a biochemical activity. Therefore in most cases FRET measurements should only be compared either to explicitly modeled probes or to concentrations of products of the biochemical activity, but not to activities themselves. Importantly, we find that FRET measured by standard intensity-based, ratiometric methods is inherently non-linear with respect to the fraction of probes undergoing FRET. Alternatively, we find that quantifying FRET either via (1) fluorescence lifetime imaging (FLIM) or (2) ratiometric methods where the donor emission intensity is divided by the directly-excited acceptor emission intensity (denoted Ralt) is linear with respect to the fraction of probes undergoing FRET. This linearity property allows one to calculate the fraction of active probes based on the FRET measurement. Thus, our results suggest that either FLIM or ratiometric methods based on Ralt are the preferred techniques for obtaining quantitative data from FRET probe experiments for mathematical modeling purposes.
Niclosamide Suppresses Cancer Cell Growth By Inducing Wnt Co-Receptor LRP6 Degradation and Inhibiting the Wnt/Î²-Catenin PathwayLu, Wenyan; Lin, Cuihong; Roberts, Michael J.; Waud, William R.; Piazza, Gary A.; Li, Yonghe; Mei, Lin; Department of Neurology; College of Graduate Studies (2011-12-16)The Wnt/b-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/b-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/b-catenin signaling, although the mechanism was not well defined. We found that niclosamide was able to suppress LRP6 expression and phosphorylation, block Wnt3A-induced b-catenin accumulation, and inhibit Wnt/b-catenin signaling in HEK293 cells. Furthermore, the inhibitory effects of niclosamide on LRP6 expression/phosphorylation and Wnt/b-catenin signaling were conformed in human prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. Moreover, we showed that the mechanism by which niclosamide suppressed LRP6 resulted from increased degradation as evident by a shorter half-life. Finally, we demonstrated that niclosamide was able to induce cancer cell apoptosis, and displayed excellent anticancer activity with IC50 values less than 1 mM for prostate PC-3 and DU145 and breast MDA-MB-231 and T-47D cancer cells. The IC50 values are comparable to those shown to suppress the activities of Wnt/b-catenin signaling in prostate and breast cancer cells. Our data indicate that niclosamide is a unique small molecule Wnt/b-catenin signaling inhibitor targeting the Wnt co-receptor LRP6 on the cell surface, and that niclosamide has a potential to be developed a novel chemopreventive or therapeutic agent for human prostate and breast cancer.