Reelin is a platelet protein and functions as a positive regulator of platelet spreading on fibrinogen

Abstract

Abnormalities of platelet functions have been linked to reelin-impaired neuronal disorders. However, little attention has been given to understanding the interplay between reelin and platelet. In this study, reelin was found to present in the human platelets and megakaryocyte-like leukemic cells. Reelin-binding assays revealed that extracellular reelin can interact with platelets through the receptor belonging to the low density lipoprotein receptor gene family. The reelin-to-platelet interactions enhance platelet spreading on fibrinogen concomitant with the augmentation of lamellipodia formation and F-actin bundling. In contrast, reelin has no effect on integrin alphaIIbbeta3 activation and agonist-induced platelet aggregation. Molecular analysis revealed that the up-regulation of Rac1 activity and the inhibition of protein kinase C delta-Thr505 phosphorylation are important for reelin-mediated enhancement of platelet spreading on fibrinogen. These findings demonstrate for the first time that reelin is present in platelets and the reelin-to-platelet interactions play a novel role in platelet signaling and functions.

Loss of Reelin protects against atherosclerosis by reducing leukocyte–endothelial cell adhesion and lesion macrophage accumulation

“…Reelin, a regulator of brain development and synaptic neuromodulator that signals through ApoE receptors, is also abundant in the liver and present at substantial concentrations in the circulation (21, 23, 24). In the present work, we employed two distinct types of Reelin conditional knockout mice to determine how Reelin affected atherosclerosis.…”

“…Although atherosclerosis specifically affects arterial vessels, as opposed to the venous system, and is marked by the subendothelial accumulation of lipids and lipid-laden foam cells (40), it shares the recruitment of circulating leukocytes and monocytes to the developing and progressing lesions with other inflammatory processes that involve the vasculature. Reelin has been reported to affect thrombosis and hemostasis (23, 24). Here we have shown that Reelin promotes atherosclerosis by increasing leukocyte adhesion to the vascular endothelium through increased abundance of the major adhesion molecules that are induced during atherogenesis and which promote the accumulation of macrophages in the lesions - ICAM-1, VCAM-1, and E-selectin (34, 35, 41, 42).…”

“…Conceivable alternative strategies involve siRNA- or antisense oligonucleotide-directed ablation of peripheral Reelin production or systemic application of recombinant function-blocking decoy receptors, a strategy that is being successfully employed for anti-TNF therapy (52). In addition, removing or inhibiting circulating Reelin could be expected to further protect against thromobosis by reducing platelet adhesion (23) and clotting propensity (24), factors that also promote atherogenesis. Likewise, suppression of circulating Reelin might also be beneficial in other diseases in which excessive leukocyte/monocyte extravasation contributes to the pathology.…”

“…In the liver, Reelin is produced by stellate cells, not hepatocytes (22). It promotes platelet spreading on fibrinogen and also plays a role in coagulation by enhancing thrombin generation and the formation of fibrin clots (23, 24). There is evidence that the two receptors for Reelin, Apolipoprotein E receptor-2 (Apoer2/Lrp8) and very low-density lipoprotein receptor (Vldlr), influence atherosclerosis severity.…”

Erythroid differentiation is augmented in Reelin‐deficient K562 cells and homozygous reeler mice

“…Because they express Reelin [5] and are able to differentiate into lineage‐specific blood cells [19], K562 cells were used in this study to address the role of Reelin in erythroid differentiation. Western blot analysis revealed that the full‐length 420 kDa Reelin protein was elevated by NaB in a dose‐dependent manner (Fig.…”