Pituitary adenylate cyclase-activating polypeptide stimulates glial fibrillary acidic protein gene expression in cortical precursor cells by activating Ras and Rap1

Lastres‐Becker, Isabel; Fernández-Pérez, Antonio; Cebolla, Beatriz; Vallejo, Mario

doi:10.1016/j.mcn.2008.07.009

Cited by 11 publications

(16 citation statements)

References 65 publications

(99 reference statements)

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“…In cells that differentiate into neurons, expression of PAC1-R is increased, whereas the level of expression decreases in cells with a glial phenotype . PACAP-evoked differentiation of precursor cells into astrocytes is mediated by cAMP, PKC␤, and calcium, involves coactivation of Ras and Rap1, and recruits the transcriptional repressor DREAM, an activator of GFAP gene expression Lastres-Becker et al, 2008).…”

Section: Kip2mentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

et al. 2009

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Section: Kip2mentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

et al. 2009

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“…This notion was supported by three lines of evidence: First, the astrogliogenic effect of PACAP on cortical progenitors can be inhibited by the cAMP antagonist Rp-cAMPS; second, treatment of cortical progenitors with PACAP results in phosphorylation of CREB, a well known substrate for PKA; and third, PACAPinduced CREB phosphorylation can be inhibited by pretreatment with the PKA inhibitor H89 [43]. However, it soon became clear that PKA is not involved because H89 was not able to inhibit the stimulation of GFAP gene expression nor the differentiation of astrocytes induced by PACAP.…”

Section: Intracellular Camp-dependent Signaling Triggered By Pacap Inmentioning

confidence: 93%

“…This response observed after stimulation of the cAMP-dependent pathway in cortical progenitors is specifically instructive because stimulation of this second messenger pathway does not result in the differentiation of neurons or oligodendrocytes [41], although these cells retain the capacity to differentiate into neurons in response to an appropriate stimulus such as BDNF [43]. After this initial observation, a search for an extracellular ligand that could mimic the effect of cAMP was initiated.…”

Section: Generation Of Astrocytes During Brain Developmentmentioning

confidence: 99%

“…In cortical progenitors, PACAP is able to stimulate both pathways [43]. In the first case, exposure of cells to PACAP results in the activation of Rap1, which acts as an effector for cAMP-activated Epac.…”

Section: Intracellular Camp-dependent Signaling Triggered By Pacap Inmentioning

confidence: 99%

“…That Ras is stimulated in a cAMPdependent manner was demonstrated by the observation that PACAP is unable to activate Ras in the presence of RpcAMPS and that GFAP promoter stimulation by the stable cAMP analog 8Br-cAMP is significantly reduced in the presence of the dominant negative inhibitor RasN17 [43].…”

Section: Intracellular Camp-dependent Signaling Triggered By Pacap Inmentioning

confidence: 99%

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PACAP signaling to DREAM: A cAMP-Dependent Pathway that Regulates Cortical Astrogliogenesis

Vallejo

2009

Mol Neurobiol

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Astrocytes constitute a very abundant cell type in the mammalian central nervous system and play critical roles in brain function. During development, astrocytes are generated from neural progenitor cells only after these cells have generated neurons. This so called gliogenic switch is tightly regulated by intrinsic factors that inhibit the generation of astrocytes during the neurogenic period. Once neural progenitors acquire gliogenic competence, they differentiate into astrocytes in response to specific extracellular signals. Some of these signals are delivered by neurotrophic cytokines via activation of the gp130-JAK-signal transducer and activator of transcription system, whereas others depend on the activity of pituitary adenylate cyclase-activating polypeptide (PACAP) on specific PAC1 receptors that stimulate the production of cAMP. This results in the activation of the small GTPases Rap1 and Ras, and in the cAMP-dependent entry of extracellular calcium into the cell. Calcium, in turn, stimulates the transcription factor downstream regulatory element antagonist modulator (DREAM), which is bound to specific sites of the promoter of the glial fibrillary acidic protein gene, stimulating its expression during astrocyte differentiation. Lack of DREAM in vivo results in alterations in the number of neurons and astrocytes generated during development. Thus, the PACAP-cAMP-Ca(2+)-DREAM signaling cascade constitutes an important pathway to activate glial-specific gene expression during astrocyte differentiation.

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Ataxin-2 Modulates the Levels of Grb2 and Src but Not Ras Signaling

et al. 2013

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Ataxin-2 (ATXN2) is implicated mainly in mRNA processing. Some ATXN2 associates with receptor tyrosine kinases (RTK), inhibiting their endocytic internalization through interaction of proline-rich domains (PRD) in ATXN2 with SH3 motifs in Src. Gain of function of ATXN2 leads to neuronal atrophy in the diseases spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Conversely, ATXN2 knockout (KO) mice show hypertrophy and insulin resistance. To elucidate the influence of ATXN2 on trophic regulation, we surveyed interactions of ATXN2 with SH3 motifs from numerous proteins and observed a novel interaction with Grb2. Direct binding in glutathione S-transferase (GST) pull-down assays and coimmunoprecipitation of the endogenous proteins indicated a physiologically relevant association. In SCA2 patient fibroblasts, Grb2 more than Src protein levels were diminished, with an upregulation of both transcripts suggesting enhanced protein turnover. In KO mouse embryonal fibroblasts (MEF), the protein levels of Grb2 and Src were decreased. ATXN2 absence by itself was insufficient to significantly change Grb2-dependent signaling for endogenous Ras levels, Ras-GTP levels, and kinetics as well as MEK1 phosphorylation, suggesting that other factors compensate for proliferation control. In KO tissue with postmitotic neurons, a significant decrease of Src protein levels is prominent rather than Grb2. ATXN2 mutations modulate the levels of several components of the RTK endocytosis complex and may thus contribute to alter cell proliferation as well as translation and growth.

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Pituitary adenylate cyclase-activating polypeptide stimulates glial fibrillary acidic protein gene expression in cortical precursor cells by activating Ras and Rap1

Abstract: Thus, cAMP-dependent PACAP-induced GFAP expression during astrocytogenesis involves the coordinated activation of both Ras and Rap1, but activation of either one of them in isolation is not sufficient to trigger this response.3

Cited by 11 publications

References 65 publications

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

PACAP signaling to DREAM: A cAMP-Dependent Pathway that Regulates Cortical Astrogliogenesis

Ataxin-2 Modulates the Levels of Grb2 and Src but Not Ras Signaling

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