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Review
. 2016 Jun 30:10:166.
doi: 10.3389/fncel.2016.00166. eCollection 2016.

Canonical and Non-canonical Reelin Signaling

Hans H Bock  1 , Petra May  1
Affiliations
Review

Canonical and Non-canonical Reelin Signaling

Hans H Bock et al. Front Cell Neurosci. .

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.

Keywords: Alzheimer disease; Eph receptor; amyloid precursor protein; coreceptor; integrin; neuronal development; protein kinase; synaptic plasticity.

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Figures

Figure 1
Figure 1
Core Reelin signaling pathway. A simplified scheme of Reelin-induced signaling events in neurons is shown. Based on a combination of phenotypic analysis of mouse mutants and biochemical studies a core Reelin signaling pathway was identified, where lipoprotein receptors interact with the phosphotyrosine-binding (PTB) domain of Disabled-1 (Dab1) via the NPXY motif in their intracellular domains. Oligomerized Reelin induces clustering of the receptor-Dab1 complexes, which induces tyrosine phosphorylation of Dab1 by Src family kinases (SFK) at different sites. This leads to site-specific modification of downstream signaling effectors, which is discussed in more detail in the text. The reciprocal activation of Src kinases (SFK) and Dab1, which underlies the prolonged increase of Dab1 phosphorylation after Reelin stimulation, is negatively regulated by p-Dab1 ubiquitinylation and degradation. It is unclear to what degree Apoer2 and Vldlr are coclustered by Reelin. Inhibition of the serine/threonine kinase Gsk3β via Akt was the first described lipoprotein receptor- and Dab1-dependent linear Reelin signaling cascade in neurons, which targets the cytoskeleton. Reelin binds to additional transmembrane proteins (coreceptors) that also interact with Dab1, which are not essential for the tyrosine phosphorylation of Dab1 but might be involved in receptor crosstalk and/or activation of additional downstream effectors. Long-lasting changes in responsive cells are induced by transcriptional regulation, which involves the gamma-secretase mediated release of receptor intracellular domains. The regulation of transmembrane proteins (N-Cadherin, Nectin) downstream of a Reelin-Dab1-Crk/CrkL-Rap1-dependent signaling cascade has been shown to be essential for Reelin’s role during neurodevelopment.
Figure 2
Figure 2
Canoncial and non-canonical Reelin signaling. Alternative schemes of Reelin signaling are shown. Examples for the different concepts are discussed in the text. (A) The canonical signaling pathway involves direct binding of Reelin via its central fragment to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr), which induces tyrosine phosphorylation of Dab1. This leads to the modulation of downstream signaling effectors. In this model, recruitment of SFK by Reelin-binding coreceptors is not required. (B) Other transmembrane receptors can be indirectly activated by Reelin-Dab1 dependent signaling in an inside-out manner; here, the receptors function as downstream effectors of the canonical Reelin signaling cascade. (C) In this model, the recruitment of SFK requires Reelin-binding coreceptors in addition to the canonical Reelin receptors Apoer2 and Vldlr. Cadherin-related neuronal receptors (CNR) or ephrin B proteins have been suggested to represent such putative obligatory coreceptors (see text for details). (D) Non-canonical activation of Dab1 signaling has been reported; this can either involve other ligands than Reelin that signal via Apoer2 or Vldlr; alternative Reelin receptors, as depicted here; or transphosphorylation of Dab1 via receptor tyrosine kinases. Reelin can also bind to alternative receptors, e.g., via its aminoterminal fragment, and induce Dab1-independent signaling cascades. (E) Dab1-independent Reelin signaling via Apoer2 or Vldlr has been postulated, based on phenotypic differences between the respective mouse knockout models. Apoer2-or Vldlr-specific Reelin signaling events have been reported as well, which could involve as yet unidentified receptor-specific adapter proteins. (F) Downstream effectors of canonical Reelin signaling function as convergence points for various upstream regulators, allowing responsive cells to fine-tune their response to external and internal stimuli in a context-dependent manner.
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