Dab1 is an intracellular adaptor protein essential for brain formation during development. Tyrosine phosphorylation in Dab1 plays important roles in neuronal migration, dendrite development, and synapse formation by affecting several downstream pathways. Reelin is the best-known extracellular protein that induces Dab1 phosphorylation. However, whether other upstream molecule(s) contribute to Dab1 phosphorylation remains largely unknown. Here, we found that EphA4, a member of the Eph family of receptor-type tyrosine kinases, induced Dab1 phosphorylation when co-expressed in cultured cells. Tyrosine residues phosphorylated by EphA4 were the same as those phosphorylated by Reelin in neurons. The autophosphorylation of EphA4 was necessary for Dab1 phosphorylation. We also found that EphA4-induced Dab1 phosphorylation was mediated by the activation of the Src family tyrosine kinases. Interestingly, Dab1 phosphorylation was not observed when EphA4 was activated by ephrin-A5 in cultured cortical neurons, suggesting that Dab1 is localized in a different compartment in them. EphA4-induced Dab1 phosphorylation may occur under limited and/or pathological conditions in the brain.
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Biochemical characterizations of the central fragment of human Reelin and identification of amino acid residues involved in its secretion.
J Biochem
November 2024
Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
Secreted protein Reelin is implicated in neuropsychiatric disorders and its supplementation ameliorates neurological symptoms in mouse disease models. Recombinant human Reelin protein may be useful for the treatment of human diseases, but its properties remain uncharacterized. Here, we report that full-length human Reelin was well secreted from transfected cells and was able to induce Dab1 phosphorylation.
View Article and Find Full Text PDFEphA4 Induces the Phosphorylation of an Intracellular Adaptor Protein Dab1 via Src Family Kinases.
Biol Pharm Bull
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Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University.
Dab1 is an intracellular adaptor protein essential for brain formation during development. Tyrosine phosphorylation in Dab1 plays important roles in neuronal migration, dendrite development, and synapse formation by affecting several downstream pathways. Reelin is the best-known extracellular protein that induces Dab1 phosphorylation.
View Article and Find Full Text PDFApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer's disease.
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Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, 20892, USA.
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Central repeat fragment of reelin leads to active reelin intracellular signaling and rescues cognitive deficits in a mouse model of reelin deficiency.
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Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL 33612, USA. Electronic address:
Reelin and its receptor, ApoER2, play important roles in prenatal brain development and postnatally in synaptic plasticity, learning, and memory. Previous reports suggest that reelin's central fragment binds to ApoER2 and receptor clustering is involved in subsequent intracellular signaling. However, limitations of currently available assays have not established cellular evidence of ApoER2 clustering upon binding of the central reelin fragment.
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Nat Med
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Neuroscience Group of Antioquia, Medicine School, University of Antioquia, Medellín, Colombia.
We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation.
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