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

Mantuano, Elisabetta; Lam, Michael S.; Gonias, Steven L.

doi:10.1074/jbc.m113.509133

Cited by 73 publications

(142 citation statements)

References 55 publications

Supporting

Mentioning

133

Contrasting

Order By: Relevance

“…In neurons, LRP1 signaling requires the NMDA-R as an essential co-receptor (Bacskai et al, 2000;Qiu et al, 2002;Samson et al, 2008;Martin et al, 2008;Sheng et al, 2008;Mantuano et al, 2013). Other LRP1 co-receptors in neurons include Trk receptors and p75 NTR (Shi et al, 2009;Yoon et al, 2013;Stiles et al, 2013).…”

Section: Nmda-r Is Necessary For Lrp1 Signaling In Schwann Cellsmentioning

confidence: 99%

“…In neurons, tPA can trigger cell signaling through a direct interaction with the NMDA-R, independently of LRP1 (Nicole et al, 2001;Macrez et al, 2010;Ng et al, 2012;Mantuano et al, 2013). To determine whether the NMDA-R signals in response to tPA, independently of LRP1 in Schwann cells, we treated Schwann cells with 12 nM EI-tPA in the presence or absence of RAP for up to 60 min.…”

Section: Nmda-r Is Necessary For Lrp1 Signaling In Schwann Cellsmentioning

confidence: 99%

“…Based on its interaction with LRP1, the NMDA-R functions as an essential signaling co-receptor for LRP1 ligands, including α 2 -macroglobulin (α 2 M), tissue-type plasminogen activator (tPA) and apolipoprotein E (Bacskai et al, 2000;Qiu et al, 2002;Samson et al, 2008;Martin et al, 2008;Sheng et al, 2008;Mantuano et al, 2013). LRP1 ligands have been implicated in neuronal survival (Hayashi et al, 2007;Fuentealba et al, 2009) and in neurite outgrowth (Mantuano et al, 2008a,b;Shi et al, 2009;Yoon et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…LRP1 ligands have been implicated in neuronal survival (Hayashi et al, 2007;Fuentealba et al, 2009) and in neurite outgrowth (Mantuano et al, 2008a,b;Shi et al, 2009;Yoon et al, 2013). Unlike other LRP1 ligands, tPA interacts directly with the NMDA-R, independently of LRP1, triggering cell signaling, albeit with delayed kinetics (Nicole et al, 2001;Macrez et al, 2010;Ng et al, 2009;Mantuano et al, 2013). NR1 subunit cleavage is reported to be involved in the mechanism by which tPA activates the NMDA-R; however, NR1 cleavage might not be necessary (Nicole et al, 2001;Mantuano et al, 2008a,b).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

Mantuano

Lam

Shibayama

et al. 2015

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

NMDA receptors (NMDA-Rs) are ionotropic glutamate receptors, which associate with LDL-receptor-related protein-1 (LRP1) to trigger cell signaling in response to protein ligands in neurons. Here, we demonstrate for the first time that the NMDA-R is expressed by rat Schwann cells and functions independently and with LRP1 to regulate Schwann cell physiology. The NR1 (encoded by GRIN1) and NR2b (encoded by GRIN2B) NMDA-R subunits were expressed by cultured Schwann cells and upregulated in sciatic nerves following crush injury. The ability of LRP1 ligands to activate ERK1/2 (also known as MAPK3 and MAPK1, respectively) and promote Schwann cell migration required the NMDA-R. NR1 gene silencing compromised Schwann cell survival. Injection of the LRP1 ligands tissue-type plasminogen activator (tPA, also known as PLAT) or MMP9-PEX into crush-injured sciatic nerves activated ERK1/2 in Schwann cells in vivo, and the response was blocked by systemic treatment with the NMDA-R inhibitor MK801. tPA was unique among the LRP1 ligands examined because tPA activated cell signaling and promoted Schwann cell migration by interacting with the NMDA-R independently of LRP1, albeit with delayed kinetics. These results define the NMDA-R as a Schwann cell signaling receptor for protein ligands and a major regulator of Schwann cell physiology, which may be particularly important in peripheral nervous system (PNS) injury.

show abstract

Section: Nmda-r Is Necessary For Lrp1 Signaling In Schwann Cellsmentioning

confidence: 99%

Section: Nmda-r Is Necessary For Lrp1 Signaling In Schwann Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

Mantuano

Lam

Shibayama

et al. 2015

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…11 In some cases, the recruitment of coreceptors might be necessary for tPA to exert its action. 12 Several studies showed that tPA can promote neurotoxicity, 5,13 especially by an overactivation of NMDARs. 8,11,[14][15][16] However, tPA may also display prosurvival properties on neurons and oligodendrocytes 4,6,[17][18][19][20] involving either an EGFR-dependent signaling, 6 binding to Annexin-II 18 or active NMDARs.…”

mentioning

confidence: 99%

Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism

et al. 2015

View full text Add to dashboard Cite

In the central nervous system, tissue-type plasminogen activator (tPA) has been associated with both pro-death and prosurvival actions on neurons. In most cases, this has been related to exogenous tPA. In the present study, we addressed the influence of endogenous tPA. We first observed an increased transcription of tPA following either in vivo global brain ischemia in rats or in vitro oxygen glucose deprivation (OGD) on mice and rats hippocampal slices. Hippocampal slices from tPA-deficient mice were more sensitive to OGD than wild-type slices. Pharmacological approaches targeting the known receptors of tPA revealed that only the inhibition of phosphorylation of epidermal growth factor receptors (EGFRs) prevented the neuroprotective effect of endogenous tPA. This study shows that ischemic hippocampal neurons overproduce endogenous tPA as an intend to protect themselves from ischemic death, by a mechanism involving an activation of EGFRs. Thus, strategies contributing to promote either endogenous production of tPA or its associated EGFR-linked signaling pathway may have beneficial effects following brain injuries such as stroke.

show abstract

LRP1 deficiency in microglia blocks neuro‐inflammation in the spinal dorsal horn and neuropathic pain processing

Brifault

Kwon

Campana

et al. 2019

Glia

Self Cite

View full text Add to dashboard Cite

Following injury to the peripheral nervous system (PNS), microglia in the spinal dorsal horn (SDH) become activated and contribute to the development of local neuro‐inflammation, which may regulate neuropathic pain processing. The molecular mechanisms that control microglial activation and its effects on neuropathic pain remain incompletely understood. We deleted the gene encoding the plasma membrane receptor, LDL Receptor‐related Protein‐1 (LRP1), conditionally in microglia using two distinct promoter‐Cre recombinase systems in mice. LRP1 deletion in microglia blocked development of tactile allodynia, a neuropathic pain‐related behavior, after partial sciatic nerve ligation (PNL). LRP1 deletion also substantially attenuated microglial activation and pro‐inflammatory cytokine expression in the SDH following PNL. Because LRP1 shedding from microglial plasma membranes generates a highly pro‐inflammatory soluble product, we demonstrated that factors which activate spinal cord microglia, including lipopolysaccharide (LPS) and colony‐stimulating factor‐1, promote LRP1 shedding. Proteinases known to mediate LRP1 shedding, including ADAM10 and ADAM17, were expressed at increased levels in the SDH after PNL. Furthermore, LRP1‐deficient microglia in cell culture expressed significantly decreased levels of interleukin‐1β and interleukin‐6 when treated with LPS. We conclude that in the SDH, microglial LRP1 plays an important role in establishing and/or amplifying local neuro‐inflammation and neuropathic pain following PNS injury. The responsible mechanism most likely involves proteolytic release of LRP1 from the plasma membrane to generate a soluble product that functions similarly to pro‐inflammatory cytokines in mediating crosstalk between cells in the SDH and in regulating neuropathic pain.

show abstract

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

Cited by 73 publications

References 55 publications

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism

LRP1 deficiency in microglia blocks neuro‐inflammation in the spinal dorsal horn and neuropathic pain processing

Contact Info

Product

Resources

About