Receptor Clustering Is Involved in Reelin Signaling

ABSTRACT The Reelin signaling cascade plays a crucial role in the correct positioning of neurons during embryonic brain development. Reelin binding to apolipoprotein E receptor 2 (ApoER2) and very-low-density-lipoprotein receptor (VLDLR) leads to phosphorylation of disabled 1 (Dab1), an adaptor protein which associates with the intracellular domains of both receptors. Coreceptors for Reelin have been postulated to be necessary for Dab1 phosphorylation. We show that bivalent agents specifically binding to ApoER2 or VLDLR are sufficient to mimic the Reelin signal. These agents induce Dab1 phosphorylation, activate members of the Src family of nonreceptor tyrosine kinases, modulate protein kinase B/Akt phosphorylation, and increase long-term potentiation in hippocampal slices. Induced dimerization of Dab1 in HEK293 cells leads to its phosphorylation even in the absence of Reelin receptors. The mechanism for and the sites of these phosphorylations are identical to those effected by Reelin in primary neurons. These results suggest that binding of Reelin, which exists as a homodimer in vivo, to ApoER2 and VLDLR induces clustering of ApoER2 and VLDLR. As a consequence, Dab1 becomes dimerized or oligomerized on the cytosolic side of the plasma membrane, constituting the active substrate for the kinase; this process seems to be sufficient to transmit the signal and does not appear to require any coreceptor.

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The functions of Reelin in membrane trafficking and cytoskeletal dynamics: implications for neuronal migration, polarization and differentiation

Biochemical Journal ◽

10.1042/bcj20160628 ◽

2017 ◽

Vol 474 (18) ◽

pp. 3137-3165 ◽

Cited By ~ 24

Author(s):

Jessica Santana ◽

María-Paz Marzolo

Keyword(s):

Membrane Trafficking ◽

Neuronal Migration ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Signaling Cascade ◽

Low Density ◽

Lipoprotein Receptor ◽

Density Lipoprotein Receptor ◽

Reelin Signaling

Reelin is a large extracellular matrix protein with relevant roles in mammalian central nervous system including neurogenesis, neuronal polarization and migration during development; and synaptic plasticity with its implications in learning and memory, in the adult. Dysfunctions in reelin signaling are associated with brain lamination defects such as lissencephaly, but also with neuropsychiatric diseases like autism, schizophrenia and depression as well with neurodegeneration. Reelin signaling involves a core pathway that activates upon reelin binding to its receptors, particularly ApoER2 (apolipoprotein E receptor 2)/LRP8 (low-density lipoprotein receptor-related protein 8) and very low-density lipoprotein receptor, followed by Src/Fyn-mediated phosphorylation of the adaptor protein Dab1 (Disabled-1). Phosphorylated Dab1 (pDab1) is a hub in the signaling cascade, from which several other downstream pathways diverge reflecting the different roles of reelin. Many of these pathways affect the dynamics of the actin and microtubular cytoskeleton, as well as membrane trafficking through the regulation of the activity of small GTPases, including the Rho and Rap families and molecules involved in cell polarity. The complexity of reelin functions is reflected by the fact that, even now, the precise mode of action of this signaling cascade in vivo at the cellular and molecular levels remains unclear. This review addresses and discusses in detail the participation of reelin in the processes underlying neurogenesis, neuronal migration in the cerebral cortex and the hippocampus; and the polarization, differentiation and maturation processes that neurons experiment in order to be functional in the adult brain. In vivo and in vitro evidence is presented in order to facilitate a better understanding of this fascinating system.

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Scavenger Receptor CD36 Directs Nonclassical Monocyte Patrolling Along the Endothelium During Early Atherogenesis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.117.309123 ◽

2017 ◽

Vol 37 (11) ◽

pp. 2043-2052 ◽

Cited By ~ 31

Author(s):

Paola M. Marcovecchio ◽

Graham D. Thomas ◽

Zbigniew Mikulski ◽

Erik Ehinger ◽

Karin A.L. Mueller ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Scavenger Receptor ◽

Density Lipoprotein ◽

Adaptor Protein ◽

Fold Increase ◽

Vascular Wall ◽

Western Diet ◽

Oxidized Lipoprotein

Objective— Nonclassical monocytes (NCM) function to maintain vascular homeostasis by crawling or patrolling along the vessel wall. This subset of monocytes responds to viruses, tumor cells, and other pathogens to aid in protection of the host. In this study, we wished to determine how early atherogenesis impacts NCM patrolling in the vasculature. Approach and Results— To study the role of NCM in early atherogenesis, we quantified the patrolling behaviors of NCM in ApoE −/− (apolipoprotein E) and C57BL/6J mice fed a Western diet. Using intravital imaging, we found that NCM from Western diet–fed mice display a 4-fold increase in patrolling activity within large peripheral blood vessels. Both human and mouse NCM preferentially engulfed OxLDL (oxidized low-density lipoprotein) in the vasculature, and we observed that OxLDL selectively induced NCM patrolling in vivo. Induction of patrolling during early atherogenesis required scavenger receptor CD36, as CD36 −/− mice revealed a significant reduction in patrolling activity along the femoral vasculature. Mechanistically, we found that CD36-regulated patrolling was mediated by a SFK (src family kinase) through DAP12 (DNAX activating protein of 12KDa) adaptor protein. Conclusions— Our studies show a novel pathway for induction of NCM patrolling along the vascular wall during early atherogenesis. Mice fed a Western diet showed increased NCM patrolling activity with a concurrent increase in SFK phosphorylation. This patrolling activity was lost in the absence of either CD36 or DAP12. These data suggest that NCM function in an atheroprotective manner through sensing and responding to oxidized lipoprotein moieties via scavenger receptor engagement during early atherogenesis.

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Intersectin 1 is a component of the Reelin pathway to regulate neuronal migration and synaptic plasticity in the hippocampus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1704447114 ◽

2017 ◽

Vol 114 (21) ◽

pp. 5533-5538 ◽

Cited By ~ 20

Author(s):

Burkhard Jakob ◽

Gaga Kochlamazashvili ◽

Maria Jäpel ◽

Aziz Gauhar ◽

Hans H. Bock ◽

...

Keyword(s):

Synaptic Plasticity ◽

Neuronal Migration ◽

Pyramidal Neurons ◽

Neurological Diseases ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Long Term Potentiation ◽

Downstream Signaling ◽

Radial Glial ◽

Reelin Signaling

Brain development and function depend on the directed and coordinated migration of neurons from proliferative zones to their final position. The secreted glycoprotein Reelin is an important factor directing neuronal migration. Loss of Reelin function results in the severe developmental disorder lissencephaly and is associated with neurological diseases in humans. Reelin signals via the lipoprotein receptors very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), but the exact mechanism by which these receptors control cellular function is poorly understood. We report that loss of the signaling scaffold intersectin 1 (ITSN1) in mice leads to defective neuronal migration and ablates Reelin stimulation of hippocampal long-term potentiation (LTP). Knockout (KO) mice lacking ITSN1 suffer from dispersion of pyramidal neurons and malformation of the radial glial scaffold, akin to the hippocampal lamination defects observed in VLDLR or ApoER2 mutants. ITSN1 genetically interacts with Reelin receptors, as evidenced by the prominent neuronal migration and radial glial defects in hippocampus and cortex seen in double-KO mice lacking ITSN1 and ApoER2. These defects were similar to, albeit less severe than, those observed in Reelin-deficient or VLDLR/ ApoER2 double-KO mice. Molecularly, ITSN1 associates with the VLDLR and its downstream signaling adaptor Dab1 to facilitate Reelin signaling. Collectively, these data identify ITSN1 as a component of Reelin signaling that acts predominantly by facilitating the VLDLR-Dab1 axis to direct neuronal migration in the cortex and hippocampus and to augment synaptic plasticity.

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Prothrombotic Platelet Signaling by the Scavenger Receptor, CD36.

Blood ◽

10.1182/blood.v110.11.3642.3642 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3642-3642

Author(s):

Kan Chen ◽

Maria Febbraio ◽

Roy Silverstein

Keyword(s):

Platelet Activation ◽

Tyrosine Kinases ◽

Kinase Inhibitor ◽

Low Density Lipoprotein ◽

Scavenger Receptor ◽

Density Lipoprotein ◽

Adenosine Diphosphate ◽

Mapk Signaling ◽

Signaling Cascade

Abstract The scavenger receptor CD36 binds a broad array of ligands, including oxidized low density lipoprotein (oxLDL), thrombospondin-1, fatty acids and apoptotic cells. CD36 was first isolated and characterized structurally from platelets, but the functional role of CD36 on platelets remains relatively obscure. We previously determined that treating platelets with oxLDL activated platelets and that activation was not seen in CD36-null platelets. Using a pharmacological inhibitor we now show that inhibition of JNK MAP kinase abrogated the activation of platelets by oxLDL. This effect was specific to oxLDL-mediated activation because this inhibitor had minimal effect on platelet activation by other classic agonists as exemplified by adenosine diphosphate (ADP). We demonstrated by immunoblotting that JNK2 and its upstream activator MKK4 were phosphorylated in the presence of oxLDL. We also found that the increase of JNK2 phosphorylation by oxLDL was diminished in CD36-null platelets. We showed that a src family kinase inhibitor (AG1879) blocked both platelet activation and JNK2 phosphorylation upon oxLDL treatment. By co-immunoprecipitation we demonstrated that CD36 recruited “active” fyn and lyn in platlets upon oxLDL treatment. These studies suggest that CD36 ligands can activate platelets through a signaling cascade involving src family tyrosine kinases and MAPK signaling molecules such as MKK4 and JNK2. OxLDL forms in the setting of hyperlipidemia and inflammation and plays an important role in atherosclerosis. A common characteristic of atherosclerosis is a prothrombotic state. Our results suggested that a specific signaling cascade activated by CD36 ligands generated in pathological states may contribute to a prothrombotic phenotype in vivo.

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Reelin Signaling Facilitates Maturation of CA1 Glutamatergic Synapses

Journal of Neurophysiology ◽

10.1152/jn.00869.2006 ◽

2007 ◽

Vol 97 (3) ◽

pp. 2312-2321 ◽

Cited By ~ 66

Author(s):

Shenfeng Qiu ◽

Edwin J. Weeber

Keyword(s):

Low Density Lipoprotein ◽

Hippocampal Slices ◽

Density Lipoprotein ◽

Functional Coupling ◽

Genotypic Differences ◽

Low Density ◽

Lipoprotein Receptor ◽

Low Density Lipoprotein Receptor ◽

Density Lipoprotein Receptor ◽

Reelin Signaling

Reelin signaling through the low-density lipoprotein receptor family members, apoliproprotein E receptor 2 (apoER2) and very-low-density lipoprotein receptor (VLDLR), plays a pivotal role in dictating neuronal lamination during embryonic brain development. Recent evidence suggests that this signaling system also plays a role in the postnatal brain to modulate synaptic transmission, plasticity, and cognitive behavior, mostly likely due to a functional coupling with N-methyl-d-aspartate (NMDA) receptors. In this study, we investigated the effects of reelin on the maturation of CA1 glutamatergic function using electrophysiological and biochemical approaches. In cultured hippocampal slices, reelin treatment increased the amplitude of AMPAR-mediated miniature excitatory postsynaptic currents and the evoked AMPA/NMDA receptor current ratios. In addition, reelin treatment also reduced the number of silent synapses, facilitated a developmental switch from NR2B to NR2A of NMDARs, and increased surface expression of AMPARs in CA1 tissue. In cultured hippocampal neurons from reeler embryos, reduced numbers of AMPAR subunit GluR1 and NMDAR subunit NR1 clustering were observed compared with those obtained from wild-type embryos. Supplementing reelin in the reeler culture obliterated these genotypic differences. These results demonstrate that reelin- and lipoprotein receptor-mediated signaling may operate during developmental maturation of hippocampal glutamatergic function and thus represent a potential important mechanism for controlling synaptic strength and plasticity in the postnatal hippocampus.

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Oxidation of Plasma Low-Density Lipoprotein Accelerates Its Accumulation and Degradation in the Arterial Wall In Vivo

Circulation ◽

10.1161/01.cir.94.7.1698 ◽

1996 ◽

Vol 94 (7) ◽

pp. 1698-1704 ◽

Cited By ~ 46

Author(s):

Klaus Juul ◽

Lars B. Nielsen ◽

Klaus Munkholm ◽

Steen Stender ◽

Børge G. Nordestgaard

Keyword(s):

Arterial Wall ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density

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Interaction of 4-hydroxynonenal-modified low-density lipoproteins with the fibroblast apolipoprotein B/E receptor

Biochemical Journal ◽

10.1042/bj2340245 ◽

1986 ◽

Vol 234 (1) ◽

pp. 245-248 ◽

Cited By ~ 31

Author(s):

W Jessup ◽

G Jurgens ◽

J Lang ◽

H Esterbauer ◽

R T Dean

Keyword(s):

Apolipoprotein B ◽

Negative Charge ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Low Density ◽

Lipid Peroxidation Product ◽

Modified Low Density Lipoproteins ◽

Peroxidation Product

The incorporation of the lipid peroxidation product 4-hydroxynonenal into low-density lipoprotein (LDL) increases the negative charge of the particle, and decreases its affinity for the fibroblast LDL receptor. It is suggested that this modification may occur in vivo, and might promote atherogenesis.

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