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      Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3

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          Abstract

          Reelin is an extracellular matrix (ECM) protein that is essential for neuron migration and positioning. The expression of reelin in multiple myeloma (MM) cells and its association with cell adhesion and survival were investigated. Overexpression, siRNA knockdown, and the addition of recombinant protein of reelin were used to examine the function of reelin in MM cells. Clinically, high expression of reelin was negatively associated with progression-free survival and overall survival. Functionally, reelin promoted the adhesion of MM cells to fibronectin via activation of α5β1 integrin. The resulting phosphorylation of Focal Adhesion Kinase (FAK) led to the activation of Src/Syk/STAT3 and Akt, crucial signaling molecules involved in enhancing cell adhesion and protecting cells from drug-induced cell apoptosis. These findings indicate reelin's important role in the activation of integrin-β1 and STAT3/Akt pathways in multiple myeloma and highlight the therapeutic potential of targeting reelin/integrin/FAK axis.

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          Most cited references48

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          A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.

          The autosomal recessive mouse mutation reeler leads to impaired motor coordination, tremors and ataxia. Neurons in affected mice fail to reach their correct locations in the developing brain, disrupting the organization of the cerebellar and cerebral cortices and other laminated regions. Here we use a previously characterized reeler allele (rl(tg)) to close a gene, reelin, deleted in two reeler alleles. Normal but not mutant mice express reelin in embryonic and postnatal neurons during periods of neuronal migration. The encoded protein resembles extracellular matrix proteins involved in cell adhesion. The reeler phenotype thus seems to reflect a failure of early events associated with brain lamination which are normally controlled by reelin.
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            Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.

            Layering of neurons in the cerebral cortex and cerebellum requires Reelin, an extracellular matrix protein, and mammalian Disabled (mDab1), a cytosolic protein that activates tyrosine kinases. Here, we report the requirement for two other proteins, cell surface receptors termed very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). Both receptors can bind mDab1 on their cytoplasmic tails and are expressed in cortical and cerebellar layers adjacent to layers that express Reelin. mDab1 expression is upregulated in knockout mice that lack both VLDLR and ApoER2. Inversion of cortical layers and absence of cerebellar foliation in these animals precisely mimic the phenotype of mice lacking Reelin or mDab1. These findings suggest that VLDLR and ApoER2 participate in transmitting the extracellular Reelin signal to intracellular signaling processes initiated by mDab1.
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              Reelin and brain development.

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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                1 March 2016
                3 February 2016
                : 7
                : 9
                : 9844-9858
                Affiliations
                1 Key Laboratory of Medical Immunology, Ministry of Health, Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
                2 Peking University Institute of Hematology, People's Hospital, Beijing 100044, China
                3 Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
                4 Jining No.1 People's Hospital, Jining, Shandong 272011, China
                5 Hangzhou Cancer Hospital, Hang Zhou 310002, China
                Author notes
                Article
                7151
                10.18632/oncotarget.7151
                4891088
                26848618
                c6d9c500-36e8-4932-9c9b-cf8fa02fac8e
                Copyright: © 2016 Lin et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 September 2015
                : 23 January 2016
                Categories
                Research Paper

                Oncology & Radiotherapy
                multiple myeloma,reelin,adhesion,integrin,stat3
                Oncology & Radiotherapy
                multiple myeloma, reelin, adhesion, integrin, stat3

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