Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain

Department of Pathology and Cell Biology Program, Case Western Reserve University, Cleveland, OH 44106, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 11/2005; 171(2):327-35. DOI: 10.1083/jcb.200505078
Source: PubMed


Amyloid precursor protein (APP), implicated in Alzheimer's disease, is a trans-membrane protein of undetermined function. APP is cleaved by gamma-secretase that releases the APP intracellular domain (AICD) in the cytoplasm. In vitro studies have implicated AICD in cell signaling and transcriptional regulation, but its biologic relevance has been uncertain and its in vivo function has not been examined. To investigate its functional role, we generated AICD transgenic mice, and found that AICD causes significant biologic changes in vivo. AICD transgenic mice show activation of glycogen synthase kinase-3beta (GSK-3beta) and phosphorylation of CRMP2 protein, a GSK-3beta substrate that plays a crucial role in Semaphorin3a-mediated axonal guidance. Our data suggest that AICD is biologically relevant, causes significant alterations in cell signaling, and may play a role in axonal elongation or pathfinding.

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    • "Together with Fe65 and Tip60, AICD forms a transcriptionally active protein complex that has been reported to promote glycogen synthase kinase 3b (GSK3b) gene expression [ [143]. Interestingly, while signaling associated with AICD transcription appears to favor GSK3b activation [51,144,145], retaining AICD at the membrane would favor inhibition of GSK3b cascade [30]. It has been proposed that AICD generated through preferential endosomal BACE1 cleavage can be translocated to the nucleus to induce signaling, while production of AICD through sequential cleavage by /-secretase at the plasma membrane would perhaps favor membrane-induced signaling [30] and subsequent proteasomal degradation [97,146]. "
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    • "Here we provide evidence that the APP/AICD system contributes to regulate the GSK3β activity in trisomic aNPCs. This is in agreement with a study that demonstrated the activation of GSK3β and phosphorylation of CRMP2 in transgenic mice expressing AICD (Ryan and Pimplikar, 2005). Since the levels of mRNA transcripts and total protein levels of GSK3β were not changed in trisomic mice, the AICD-dependent modulation of GSK3β activation must be mediated by a non-transcriptional mechanism. "
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    • "In addition, PS1 regulates kinesin-related axonal transport by a mechanism involving GSK-3β activity (Ryan and Pimplikar, 2005) and the modulation of its role in controlling kinesin binding to microtubules at sites of vesicle release (Pigino et al., 2003). "
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