Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris

Fernández-Castañeda, Anthony; Arandjelovic, Sanja; Stiles, Travis L.; Schlobach, Ryan K.; Mowen, Kerri; Gonias, Steven L.; Gaultier, Alban

doi:10.1074/jbc.m112.384693

Cited by 52 publications

(59 citation statements)

References 49 publications

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“…Cells in culture produce LRP1 ligands (48,56). These ligands may activate LRP1 signaling to some degree in the absence of added proteins, such as EI-tPA or ␣ 2 M*.…”

Section: Discussionmentioning

confidence: 99%

LRP1 Assembles Unique Co-receptor Systems to Initiate Cell Signaling in Response to Tissue-type Plasminogen Activator and Myelin-associated Glycoprotein

Mantuano

Lam

Gonias

2013

Journal of Biological Chemistry

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131

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Background: LRP1 is a cell signaling receptor in neurons. Results: LRP1, NMDA receptor, and Trk compose a single system, activating cell signaling in response to tPA and ␣ 2 -macroglobulin. MAG binding to LRP1 recruits p75NTR but not Trk. Conclusion: Ligand-specific co-receptor recruitment explains how LRP1 activates distinct cell signaling pathways in response to different ligands. Significance: Distinct co-receptor assemblies allow LRP1 to regulate the cellular response to its microenvironment.

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“…Cells in culture produce LRP1 ligands (48,56). These ligands may activate LRP1 signaling to some degree in the absence of added proteins, such as EI-tPA or ␣ 2 M*.…”

Section: Discussionmentioning

confidence: 99%

LRP1 Assembles Unique Co-receptor Systems to Initiate Cell Signaling in Response to Tissue-type Plasminogen Activator and Myelin-associated Glycoprotein

Mantuano

Lam

Gonias

2013

Journal of Biological Chemistry

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131

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“…We expressed CCR-2 and CCR-4 as Fc-fusion proteins, as previously described (38). In brief, CCR-2 and CCR-4 were amplified by PCR Perhaps the most clinically relevant observation of this study was the demonstration of ANG2002-mediated relief of neuropathic and bone cancer pain, both of which are known to be refractory to traditional analgesic approaches (73)(74)(75)(76).…”

Section: Lrp1-dependent Binding and Uptake Of An2 And Ang2002mentioning

confidence: 99%

“…To examine the binding of An2 and ANG2002 to LRP1 in a purified system, we expressed the clusters of complement-like repeats in LRP1, which are responsible for the majority of LRP1-ligand interactions, as Fc fusion proteins (36)(37)(38). Fc-LRP1 clusters II and IV (CCR-2 and CCR-4, respectively) both demonstrated increased binding of 125 I-labeled An2 compared with free Fc, with preferential binding for CCR-4 ( Figure 2C).…”

Section: Figurementioning

confidence: 99%

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

Demeule¹,

Beaudet²,

Régina³

et al. 2014

J. Clin. Invest.

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101

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Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor-related protein-1 (LRP1). Using in situ brain perfusion in mice, we found that the compound ANG2002, a conjugate of An2 and NT, was transported at least 10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1 and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v. ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain. At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by the development of neuropathic and bone cancer pain in animal models. The analgesic properties of ANG2002 demonstrated in this study suggest that this compound is effective for clinical management of persistent and chronic pain and establish the benefits of this technology for the development of neurotherapeutics.

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“…However, mechanisms by which LRP1 regulates macrophage physiology remain incompletely understood. LRP1 deficiency is associated with increased NFκB activity in passaged cell lines (12); however, "loss of function" model systems do not address the role of LRP1 as a receptor for diverse ligands (7,14). In neurons and neuron-like cells, different LRP1 ligands elicit distinct cell-signaling responses by engaging separate LRP1 coreceptors (15)(16)(17).…”

mentioning

confidence: 99%

LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response

Mantuano

Brifault

Lam

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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112

160

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LDL receptor-related protein-1 (LRP1) is an endocytic and cellsignaling receptor. In mice in which LRP1 is deleted in myeloid cells, the response to lipopolysaccharide (LPS) was greatly exacerbated. LRP1 deletion in macrophages in vitro, under the control of tamoxifen-activated Cre-ER T fusion protein, robustly increased expression of proinflammatory cytokines and chemokines. In LRP1-expressing macrophages, proinflammatory mediator expression was regulated by LRP1 ligands in a ligand-specific manner. The LRP1 agonists, α 2 -macroglobulin and tissue-type plasminogen activator, attenuated expression of inflammatory mediators, even in the presence of LPS. The antagonists, receptor-associated protein (RAP) and lactoferrin (LF), and LRP1-specific antibody had the entirely opposite effect, promoting inflammatory mediator expression and mimicking LRP1 deletion. NFκB was rapidly activated in response to RAP and LF and responsible for the initial increase in expression of proinflammatory mediators. RAP and LF also significantly increased expression of microRNA-155 (miR-155) after a lag phase of about 4 h. miR-155 expression reflected, at least in part, activation of secondary cell-signaling pathways downstream of TNFα. Although miR-155 was not involved in the initial induction of cytokine expression in response to LRP1 antagonists, miR-155 was essential for sustaining the proinflammatory response. We conclude that LRP1, NFκB, and miR-155 function as members of a previously unidentified system that has the potential to inhibit or sustain inflammation, depending on the continuum of LRP1 ligands present in the macrophage microenvironment.LDL receptor-related protein-1 | tissue-type plasminogen activator | lipopolysaccharide | NFκB | microRNA-155

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Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris

Cited by 52 publications

References 49 publications

LRP1 Assembles Unique Co-receptor Systems to Initiate Cell Signaling in Response to Tissue-type Plasminogen Activator and Myelin-associated Glycoprotein

LRP1 Assembles Unique Co-receptor Systems to Initiate Cell Signaling in Response to Tissue-type Plasminogen Activator and Myelin-associated Glycoprotein

Conjugation of a brain-penetrant peptide with neurotensin provides antinociceptive properties

LDL receptor-related protein-1 regulates NFκB and microRNA-155 in macrophages to control the inflammatory response

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