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      Canonical and Non-canonical Reelin Signaling

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          Abstract

          Reelin is a large secreted glycoprotein that is essential for correct neuronal positioning during neurodevelopment and is important for synaptic plasticity in the mature brain. Moreover, Reelin is expressed in many extraneuronal tissues; yet the roles of peripheral Reelin are largely unknown. In the brain, many of Reelin’s functions are mediated by a molecular signaling cascade that involves two lipoprotein receptors, apolipoprotein E receptor-2 (Apoer2) and very low density-lipoprotein receptor (Vldlr), the neuronal phosphoprotein Disabled-1 (Dab1), and members of the Src family of protein tyrosine kinases as crucial elements. This core signaling pathway in turn modulates the activity of adaptor proteins and downstream protein kinase cascades, many of which target the neuronal cytoskeleton. However, additional Reelin-binding receptors have been postulated or described, either as coreceptors that are essential for the activation of the “canonical” Reelin signaling cascade involving Apoer2/Vldlr and Dab1, or as receptors that activate alternative or additional signaling pathways. Here we will give an overview of canonical and alternative Reelin signaling pathways, molecular mechanisms involved, and their potential physiological roles in the context of different biological settings.

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          RGD and other recognition sequences for integrins.

          Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins, and nearly half of the over 20 known integrins recognize this sequence in their adhesion protein ligands. Some other integrins bind to related sequences in their ligands. The integrin-binding activity of adhesion proteins can be reproduced by short synthetic peptides containing the RGD sequence. Such peptides promote cell adhesion when insolubilized onto a surface, and inhibit it when presented to cells in solution. Reagents that bind selectively to only one or a few of the RGD-directed integrins can be designed by cyclizing peptides with selected sequences around the RGD and by synthesizing RGD mimics. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, the RGD peptides and mimics can be used to probe integrin functions in various biological systems. Drug design based on the RGD structure may provide new treatments for diseases such as thrombosis, osteoporosis, and cancer.
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            Function and regulation of CREB family transcription factors in the nervous system.

            CREB and its close relatives are now widely accepted as prototypical stimulus-inducible transcription factors. In many cell types, these factors function as effector molecules that bring about cellular changes in response to discrete sets of instructions. In neurons, a wide range of extracellular stimuli are capable of activating CREB family members, and CREB-dependent gene expression has been implicated in complex and diverse processes ranging from development to plasticity to disease. In this review, we focus on the current level of understanding of where, when, and how CREB family members function in the nervous system.
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              Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.

              Apolipoprotein E is immunochemically localized to the senile plaques, vascular amyloid, and neurofibrillary tangles of Alzheimer disease. In vitro, apolipoprotein E in cerebrospinal fluid binds to synthetic beta A4 peptide (the primary constituent of the senile plaque) with high avidity. Amino acids 12-28 of the beta A4 peptide are required. The gene for apolipoprotein E is located on chromosome 19q13.2, within the region previously associated with linkage of late-onset familial Alzheimer disease. Analysis of apolipoprotein E alleles in Alzheimer disease and controls demonstrated that there was a highly significant association of apolipoprotein E type 4 allele (APOE-epsilon 4) and late-onset familial Alzheimer disease. The allele frequency of the APOE-epsilon 4 in 30 random affected patients, each from a different Alzheimer disease family, was 0.50 +/- 0.06; the allele frequency of APOE-epsilon 4 in 91 age-matched unrelated controls was 0.16 +/- 0.03 (Z = 2.44, P = 0.014). A functional role of the apolipoprotein E-E4 isoform in the pathogenesis of late-onset familial Alzheimer disease is suggested.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                30 June 2016
                2016
                : 10
                : 166
                Affiliations
                [1]Clinic of Gastroenterology and Hepatology, Heinrich-Heine-University Düsseldorf Düsseldorf, Germany
                Author notes

                Edited by: Gabriella D’Arcangelo, Rutgers, The State Univesity of New Jersey, USA

                Reviewed by: Shin-ichi Hisanaga, Tokyo Metropolitan University, Japan; Brian W. Howell, SUNY Upstate Medical University, USA

                *Correspondence: Hans H. Bock hans.bock@ 123456med.uni-duesseldorf.de
                Article
                10.3389/fncel.2016.00166
                4928174
                27445693
                9cee15be-4827-4812-94d1-07798d86c14c
                Copyright © 2016 Bock and May.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 March 2016
                : 08 June 2016
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 306, Pages: 20, Words: 19021
                Funding
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Award ID: SFB974
                Award ID: B10
                Funded by: Bundesministerium für Bildung und Forschung 10.13039/501100002347
                Award ID: ReelinSys2
                Categories
                Neuroscience
                Review

                Neurosciences
                neuronal development,synaptic plasticity,alzheimer disease,amyloid precursor protein,integrin,eph receptor,coreceptor,protein kinase

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