LR11, an LDL Receptor Gene Family Member, Is a Novel Regulator of Smooth Muscle Cell Migration

Abstract

Abstract-LR11, a member of the LDL receptor family, is highly expressed in vascular smooth muscle cells (SMCs) of the hyperplastic intima, and induces enhanced migration of SMCs in vitro via its upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. In this study, we have delineated the mechanism by which LR11 elevates the expression levels of uPAR in SMCs. Secretion of soluble LR11 is induced in SMCs during the rapidly proliferating phase, and the secreted LR11 induces the migration activities of SMCs. Both the cell-anchored and secreted forms of LR11 have the capacity to bind to and form complexes with uPAR. LR11-overexpressing cells show significantly enhanced uPAR binding, but decreased uPAR internalization. LR11 colocalizes with uPAR on the cell surface and inhibits the LDL receptor-related protein (

The Soluble Form of LR11 Protein Is a Regulator of Hypoxia-induced, Urokinase-type Plasminogen Activator Receptor (uPAR)-mediated Adhesion of Immature Hematological Cells

“…In this context, we showed previously that sLR11 derived from the cell surface enhances cell adhesion through the activation of uPAR and integrin-mediated signals (21,41,42). On the other hand, LR11 in intracellular vesicles (SorLA) is important for the intracellular traffic of amyloid␤ protein in neurons (43), and single nucleotide polymorphisms in the LR11/SORL1 gene and/or sLR11 levels in the cerebrospinal fluid have been reported to be a prospective marker of Alzheimer disease (44,45).…”

SorLA Signaling by Regulated Intramembrane Proteolysis

“…SorLA binds multiple ligands and is involved in the regulation of head activator-induced mitosis (22), migration of smooth muscle cells (23), atherosclerosis (27,45), and in the pathogenesis of Alzheimer disease (28 -31). So far the signal transduction pathways are not well understood.…”

“…Other ligands of SorLA include lipoproteins (12), PDGF-BB (23), and GDNF (24). In accordance with the multiple ligands, SorLA also seems to be involved in several functions including protein sorting (25), lipoprotein uptake (26), smooth muscle cell migration, and the development of atherosclerosis (27), but so far no signaling cascade has been identified. Recently, SorLA was identified to be involved in trafficking APP in neuronal cells.…”

Functional Organization of the Sortilin Vps10p Domain

“…Thus, Sortilin may be part of the machinery that governs cell survival in developing neuronal tissue and a key determinant in the induction of post-traumatic neuronal apoptosis (11), whereas SorLA seems implicated in the generation of Alzheimer's disease (12) as well as in atherosclerotic plaque formation (13,14). Information at the molecular and cellular level confirms that the receptors are multifunctional, bind several different ligands, and they engage in intracellular sorting as well as in endocytosis and signal transduction.…”