ErbB receptors and PKC regulate PC12 neuronal-like differentiation and sodium current elicitation

García, Lisbeth; Castillo, Cecilia; Carballo, Jeismar; Rodriguez, Yago; Forsyth, P.; Medina, Rafael; Martı́nez, Juan Carlos; Longart, Marines

doi:10.1016/j.neuroscience.2013.01.026

Cited by 8 publications

(10 citation statements)

References 69 publications

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“…The observation of the co-expression of the axonal and dendritic markers in neurites that would eventually become axons, is supported by previous findings, which have also shown the co-existence of the two markers in the neurites at pre-polarization stages, before the final axon specification (Matus et al, 1986 ; Pennypacker et al, 1991 ; Longart et al, 2009 ; Correa and Longart, 2010 ). Interestingly, in our previous work, the axonal final specification was reached when PC12 cells were treated with CM plus k252, which inhibits tyrosine kinase receptors (activated by NGF and other neurotrophins) and PKC; suggesting that other factors and signaling pathways are involved in the axonal specification and polarity processes (Longart et al, 2009 ; García et al, 2013 ).…”

Section: Discussionmentioning

confidence: 95%

“…In that work we demonstrated that specific blocking of ErbB receptors, completely abolished neurite outgrowth in CM-treated PC12 cells. Blocking of ErbB receptors also abolished sodium currents induced by CM+k252a (García et al, 2013 ). Thus, considering these previous findings we can claim that neuregulin could be the main responsible for initiation of the cell differentiation and neuritogenesis, and that pro-NGF is involved in keeping that initial differentiation stage.…”

Section: Discussionmentioning

confidence: 99%

“…Cells with neurites between 2.5 and 12 μm, were considered as differentiated with short neurites (DSN). The average total neurite length per cell was obtained by adding the length of all neurites (short and long), divided by the number of cells with neurites, as previously described (Longart et al, 2009 ; García et al, 2013 ).…”

Section: Methodsmentioning

confidence: 99%

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ProNGF derived from rat sciatic nerves downregulates neurite elongation and axon specification in PC12 cells

Trigos

Longart

García

et al. 2015

Front. Cell. Neurosci.

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Several reports have shown that a sciatic nerve conditioned media (CM) causes neuronal-like differentiation in PC12 cells. This differentiation is featured by neurite outgrowth, which are exclusively dendrites, without axon or sodium current induction. In previous studies, our group reported that the CM supplemented with a generic inhibitor for tyrosine kinase receptors (k252a) enhanced the CM-induced morphological differentiation upregulating neurite outgrowth, axonal formation and sodium current elicitation. Sodium currents were also induced by depletion of endogenous precursor of nerve growth factorr (proNGF) from the CM (pNGFd-CM). Given that sodium currents, neurite outgrowth and axon specification are important features of neuronal differentiation, in the current manuscript, first we investigated if proNGF was hindering the full PC12 cell neuronal-like differentiation. Second, we studied the effects of exogenous wild type (pNGFwt) and mutated (pNGFmut) proNGF isoforms over sodium currents and whether or not their addition to the pNGFd-CM would prevent sodium current elicitation. Third, we investigated if proNGF was exerting its negative regulation through the sortilin receptor, and for this, the proNGF action was blocked with neurotensin (NT), a factor known to compete with proNGF for sortilin. Thereby, here we show that pNGFd-CM enhanced cell differentiation, cell proportion with long neurites, total neurite length, induced axonal formation and sodium current elicitation. Interestingly, treatment of PC12 cells with wild type or mutated proNGF isoforms elicited sodium currents. Supplementing pNGFd-CM with pNGFmut reduced 35% the sodium currents. On the other hand, pNGFd-CM+pNGFwt induced larger sodium currents than pNGFd-CM. Finally, treatments with CM supplemented with NT showed that sortilin was mediating proNGF negative regulation, since its blocking induced similar effects than the pNGFd-CM treatment. Altogether, our results suggest that proNGF within the CM, is one of the main inhibitors of full neuronal differentiation, acting through sortilin receptor.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

ProNGF derived from rat sciatic nerves downregulates neurite elongation and axon specification in PC12 cells

Trigos

Longart

García

et al. 2015

Front. Cell. Neurosci.

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“…The AKT pathway regulates dendritic size and complexity (Kumar et al 2005). Importantly, PKC and SRC are regulators of both ERK and AKT (Puente et al 2006; Uht et al 2007; Hu et al 2009; Lodeiro et al 2009) and they also regulate neurite formation (Garcia et al 2013; Liao et al 2012; Zhao et al 2009; Kotani et al 2007). Taken together, our preliminary results suggest that the gene expression changes ( PRKCH, SRC ) we found in the presence of the V>L variant may lead to alterations in activity of PKA, ERK and AKT kinases, leading to deficits in dendrite formation via altered phosphorylation of neurite formation mediators.…”

Section: Discussionmentioning

confidence: 99%

Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches

et al. 2014

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Aberrant Neuregulin 1-ErbB4 signalling has been implicated in schizophrenia. We previously identified a novel schizophrenia-associated missense mutation (valine to leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation. To assess the global effects of this mutation we used lymphoblastoid cell lines from unaffected heterozygous carriers (Val/Leu) and non carriers (Val/Val). Transcriptome data showed 367 genes differentially expressed between the two groups (Val/Val N=6, Val/Leu N=5, T test, FDR (1%), alpha = 0.05, −log10 p value > 1.5). Ingenuity pathway (IPA) analyses showed inflammation and NRG1 signalling as the top pathways altered. Within NRG1 signalling, Protein Kinase C (PKC)–eta (PRKCH) and non-receptor tyrosine kinase (SRC) were down-regulated in heterozygous carriers. Novel kinome profiling (Serine/Threonine) was performed after stimulating cells (V/V N=6, V/L N=6) with ErbB4, to induce release of the NRG1 ICD, and revealed significant effects of treatment on the phosphorylation of 35 peptides. IPA showed neurite outgrowth (6 peptides) as the top annotated function. Phosphorylation of these peptides was significantly decreased in ErbB4-treated Val/Val but not in Val/Leu cells. These results show that perturbing NRG1 ICD formation has major effects on cell signalling, including inflammatory and neurite formation pathways, and may contribute significantly to schizophrenia pathophysiology.

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“…Berberine inhibits metastasis through the inhibition of PKCα signaling in breast cancer cells (Kim et al, 2012). PKC is involved in the ErbB receptor signaling in neuronal differentiation (García et al, 2013). However, the effect of berberine in tamoxifenresistant breast cancer cells and erbB signaling remains elusive and needs to be clarified further.…”

Section: Proposed Ptgs and The Mechanism Of Berberine In Overcoming Bmentioning

confidence: 99%

Identification of potential gene associated with berberine in overcoming tamoxifen resistance by functional network analysis

Hermawan¹,

Putri²

2020

J App Pharm Sci

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Previously, berberine enhanced the sensitivity ofMichigan Cancer Foundation-7 (MCF-7)-resistant breast cancer cells toward tamoxifen; however, its molecular mechanism remains unclear. The purpose of this study is to identify the potential targets and molecular mechanisms of berberine in overcoming breast cancer resistance toward tamoxifen by using a bioinformatics approach for functional network analysis. The microarray data of tamoxifen-resistant and berberine-treated MCF-7 cells were obtained from GSE67916 and GSE85871, which resulted in differentially expressed genes (DEGs). The analysis of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment by using the Database for Annotation, Visualization, and Integrated Discovery revealed that several DEGs participated in the erbB tyrosine kinase signaling pathway. The analysis of protein-protein interaction network and hub gene selection by using STRING and Cytoscape identified the top 10 genes with the highest degree score. The analysis of genetic alterations by using cBioPortal demonstrated the genetic alterations of six potential target genes, including protein kinase C alpha type (PRKCA), epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 4 (ERBB4), amphiregulin (AREG), estrogen receptor 1 (ESR1), and STAT1. Moreover, importantly, the erbB signaling is a potential target for overcoming breast cancer resistance toward tamoxifen. Further studies are required to validate the results of this study.

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ErbB receptors and PKC regulate PC12 neuronal-like differentiation and sodium current elicitation

Cited by 8 publications

References 69 publications

ProNGF derived from rat sciatic nerves downregulates neurite elongation and axon specification in PC12 cells

ProNGF derived from rat sciatic nerves downregulates neurite elongation and axon specification in PC12 cells

Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches

Identification of potential gene associated with berberine in overcoming tamoxifen resistance by functional network analysis

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