LRP1 Regulates Architecture of the Vascular Wall by Controlling PDGFRβ-Dependent Phosphatidylinositol 3-Kinase Activation

Monash University, Australia
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(9):e6922. DOI: 10.1371/journal.pone.0006922
Source: PubMed


Low density lipoprotein receptor-related protein 1 (LRP1) protects against atherosclerosis by regulating the activation of platelet-derived growth factor receptor beta (PDGFRbeta) in vascular smooth muscle cells (SMCs). Activated PDGFRbeta undergoes tyrosine phosphorylation and subsequently interacts with various signaling molecules, including phosphatidylinositol 3-kinase (PI3K), which binds to the phosphorylated tyrosine 739/750 residues in mice, and thus regulates actin polymerization and cell movement.
In this study, we found disorganized actin in the form of membrane ruffling and enhanced cell migration in LRP1-deficient (LRP1-/-) SMCs. Marfan syndrome-like phenotypes such as tortuous aortas, disrupted elastic layers and abnormally activated transforming growth factor beta (TGFbeta) signaling are present in smooth muscle-specific LRP1 knockout (smLRP1-/-) mice. To investigate the role of LRP1-regulated PI3K activation by PDGFRbeta in atherogenesis, we generated a strain of smLRP1-/- mice in which tyrosine 739/750 of the PDGFRbeta had been mutated to phenylalanines (PDGFRbeta F2/F2). Spontaneous atherosclerosis was significantly reduced in the absence of hypercholesterolemia in these mice compared to smLRP1-/- animals that express wild type PDGFR. Normal actin organization was restored and spontaneous SMC migration as well as PDGF-BB-induced chemotaxis was dramatically reduced, despite continued overactivation of TGFbeta signaling, as indicated by high levels of nuclear phospho-Smad2.
Our data suggest that LRP1 regulates actin organization and cell migration by controlling PDGFRbeta-dependent activation of PI3K. TGFbeta activation alone is not sufficient for the expression of the Marfan-like vascular phenotype. Thus, regulation of PI3 Kinase by PDGFRbeta is essential for maintaining vascular integrity, and for the prevention of atherosclerosis as well as Marfan syndrome.

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Available from: Michelle Tallquist, Oct 10, 2015
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    • "PDGFR-β and the activation of PI3K/Akt are both important for PDGF-BB to function [18], [28], [29]. We thus further tested whether the PI3K/Akt signaling pathway plays a role in the PDGF-BB-induced proliferation, migration, and angiogenesis of EPCs and whether this role is also important in the promotive effects of PDGFR-β over-expression on these PDGF-BB-induced phenotypes. "
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    ABSTRACT: The proliferation, migration, and angiogenesis of endothelial progenitor cells (EPCs) play critical roles in postnatal neovascularization and re-endothelialization following vascular injury. Here we evaluated whether the over-expression of platelet-derived growth factor receptor-β (PDGFR-β) can enhance the PDGF-BB-stimulated biological functions of EPCs through the PDGFR-β/phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. We first confirmed the expression of endogenous PDGFR-β and its plasma membrane localization in spleen-derived EPCs. We then demonstrated that the PDGFR-β over-expression in EPCs enhanced the PDGF-BB-induced proliferation, migration, and angiogenesis of EPCs. Using AG1295 (a PDGFR kinase inhibitor), LY294002 (a PI3K inhibitor), and sc-221226 (an Akt inhibitor), we further showed that the PI3K/Akt signaling pathway participates in the PDGF-BB-induced proliferation, migration, and angiogenesis of EPCs. In addition, the PI3K/Akt signaling pathway is required for PDGFR-β over-expression to enhance these PDGF-BB-induced phenotypes.
    PLoS ONE 02/2012; 7(2):e30503. DOI:10.1371/journal.pone.0030503 · 3.23 Impact Factor
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    • "FSAP is involved in cleaning PDGF protein however its activity is inhibited when it gets complexes with PN-I, this hetrodimer has an enhanced affiliation for LRP and it internalizes this protein complex, if an interactive crosstalk is established between hetrodimer and LRP's, it sequesters LRP from PDGFR as a result of which PDGFR is not internalizes an stays embedded in the plasma membrane, offering a binding site to PDGF and signal transduction initiates, henceforth PDGF is protected from cleavage by FSAP and LRP is detached from PDGFR that maintains required density of the receptors on the membrane (Muhl et al., 2007). Ahmed et al. 137 LRP works synchronously with PDGFR to initiate PI3K dependent signaling, which is essential for maintaining vascular integrity (Zhou et al., 2009). LRP is also necessary for ERK activation, so LRP works concomitantly with PDGFR, abrogated LRP blunts the activity of ERK, this aspect rules out the presumed role of ERK to be a potential candidate for kinase activity or kinase activity in LRP deficient cells (Muratoglu et al., 2010). "
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    ABSTRACT: PDGF is a growth factor and is extensively involved in multi-dimensional cellular dynamics. It switches on a plethora of molecules other than its classical pathway. It is engaged in various transitions of development however if the unleashed potentials lead astray it brings forth tumorigenesis. Conventionally, it has been assumed that the components of this signaling pathway show fidelity and act with a high degree of autonomy. However, as illustrated by the PDGF signal transduction, reinterpretation of recent data suggests that machinery is often shared between multiple pathways and other components crosstalk to each other through multiple mechanisms. There is a very indiscriminate line that demarcates between normal division and neoplasia. A number of unidentified proteins might be instrumental to this transition. The signal perpetuation is a remarkable portfolio of tumor progression.
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    • "Since sclerostin can inhibit BMPs, and Dkk1 is itself regulated by BMPs, it is likely that the failure to properly integrate BMP and Wnt signaling pathways in the absence of a normal, functional Lrp4 is responsible for the reduced limb length growth in the Lrp4 ECD mutants. Such a mechanism would be analogous to the role of LRP1 in the integration of PDGF and TGFβ signals in the vascular wall, where loss of LRP1 expression in smooth muscle cells results in the simultaneous deregulation of PDGF as well as TGFβ signalling with medial hypertrophy, elastolysis and fibrosis [57]–[59]. "
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    ABSTRACT: Lrp4 is a multifunctional member of the low density lipoprotein-receptor gene family and a modulator of extracellular cell signaling pathways in development. For example, Lrp4 binds Wise, a secreted Wnt modulator and BMP antagonist. Lrp4 shares structural elements within the extracellular ligand binding domain with Lrp5 and Lrp6, two established Wnt co-receptors with important roles in osteogenesis. Sclerostin is a potent osteocyte secreted inhibitor of bone formation that directly binds Lrp5 and Lrp6 and modulates both BMP and Wnt signaling. The anti-osteogenic effect of sclerostin is thought to be mediated mainly by inhibition of Wnt signaling through Lrp5/6 within osteoblasts. Dickkopf1 (Dkk1) is another potent soluble Wnt inhibitor that binds to Lrp5 and Lrp6, can displace Lrp5-bound sclerostin and is itself regulated by BMPs. In a recent genome-wide association study of bone mineral density a significant modifier locus was detected near the SOST gene at 17q21, which encodes sclerostin. In addition, nonsynonymous SNPs in the LRP4 gene were suggestively associated with bone mineral density. Here we show that Lrp4 is expressed in bone and cultured osteoblasts and binds Dkk1 and sclerostin in vitro. MicroCT analysis of Lrp4 deficient mutant mice revealed shortened total femur length, reduced cortical femoral perimeter, and reduced total femur bone mineral content (BMC) and bone mineral density (BMD). Lumbar spine trabecular bone volume per total volume (BV/TV) was significantly reduced in the mutants and the serum and urinary bone turnover markers alkaline phosphatase, osteocalcin and desoxypyridinoline were increased. We conclude that Lrp4 is a novel osteoblast expressed Dkk1 and sclerostin receptor with a physiological role in the regulation of bone growth and turnover, which is likely mediated through its function as an integrator of Wnt and BMP signaling pathways.
    PLoS ONE 11/2009; 4(11):e7930. DOI:10.1371/journal.pone.0007930 · 3.23 Impact Factor
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