Abstract
Background:
Reelin is a large signaling molecule that regulates the positioning of neurons in the mammalian brain. Transmission of the Reelin signal to migrating embryonic neurons requires binding to the very-low-density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor-2 (apoER2). This induces tyrosine phosphorylation of the adaptor protein Disabled-1 (Dab1), which interacts with a shared sequence motif in the cytoplasmic tails of both receptors. However, the kinases that mediate Dab1 tyrosine phosphorylation and the intracellular pathways that are triggered by this event remain unknown.
Results:
We show that Reelin activates members of the Src family of non-receptor tyrosine kinases (SFKs) and that this activation is dependent on the Reelin receptors apoER2 and VLDLR and the adaptor protein Dab1. Dab1 is tyrosine phosphorylated by SFKs, and the kinases themselves can be further activated by phosphorylated Dab1. Increased Dab1 protein expression in fyn-deficient mice implies a response to impaired Reelin signaling that is also observed in mice lacking Reelin or its receptors. However, fyn deficiency alone does not compound the neuronal positioning defect of vldlr- or apoer2-deficient mice, and this finding suggests functional compensation by other SFKs.
Conclusions:
Our results show that Dab1 is a physiological substrate as well as an activator of SFKs in neurons. Based on genetic evidence gained from multiple strains of mutant mice with defects in Reelin signaling, we conclude that activation of SFKs is a normal part of the cellular Reelin response.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Adhesion Molecules, Neuronal / genetics
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Cell Adhesion Molecules, Neuronal / metabolism*
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Cell Adhesion Molecules, Neuronal / pharmacology
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / metabolism*
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Extracellular Matrix Proteins / pharmacology
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Female
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LDL-Receptor Related Proteins
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Male
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Mice
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Mice, Mutant Strains
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Phosphorylation / drug effects
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-fyn
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Receptors, LDL / deficiency
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Receptors, LDL / genetics
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Receptors, LDL / metabolism
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Receptors, Lipoprotein / deficiency
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Receptors, Lipoprotein / genetics
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Receptors, Lipoprotein / metabolism
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Reelin Protein
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Serine Endopeptidases
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Signal Transduction
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Tyrosine / metabolism
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src-Family Kinases / drug effects
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src-Family Kinases / genetics
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src-Family Kinases / metabolism*
Substances
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Cell Adhesion Molecules, Neuronal
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Dab1 protein, mouse
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Enzyme Inhibitors
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Extracellular Matrix Proteins
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LDL-Receptor Related Proteins
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Nerve Tissue Proteins
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Proto-Oncogene Proteins
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Receptors, LDL
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Receptors, Lipoprotein
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Reelin Protein
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VLDL receptor
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low density lipoprotein receptor-related protein 8
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Tyrosine
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Fyn protein, mouse
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Proto-Oncogene Proteins c-fyn
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src-Family Kinases
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Reln protein, mouse
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Serine Endopeptidases