The LDL receptor-related protein (LRP1) couples ligand endocytosis with cell-signaling; however, the nature of the signaling response varies under specific conditions. Variability in LRP1 signaling is evident in studies of cultured neurons and neuron-like cell lines. Specific LRP1 ligands, including tissue-type plasminogen activator (tPA) and activated α2-macroglobulin, activate ERK and Akt in these cells, promoting neurite outgrowth. Myelin-derived inhibitory proteins, such as Myelin-associated Glycoprotein (MAG), also bind to LRP1; however, MAG-binding to LRP1 activates RhoA and inhibits neurite outgrowth. In this study, we analyzed the LRP1 receptor assembly responsible for ERK activation and compared this with the receptor complex that assembles in response to MAG. We found that in PC12 and N2a cells, activation of ERK by tPA strictly required LRP1. The NMDA receptor and Trk receptors also were necessary for LRP1 signaling to ERK in response to tPA. By contrast, MAG was unique in its ability to recruit p75NTR into association with LRP1. p75NTR has been previously implicated in RhoA activation and inhibition of neuronal regeneration in spinal cord injury. Although tPA and MAG both bind to the clusters of complement-like repeats (CCRs) in LRP1, the binding sites for these two ligands may not be identical. p75NTR co-immunoprecipitated with LRP1 from injured but not uninjured rodent spinal cords in vivo. Regulation of LRP1 signaling represents an important target for therapeutics development in CNS injury.

Ligand-specific co-receptor recruitment determines the signaling activity of LRP1 in response to tissue-type plasminogen activator and myelin-associated glicoprotein / Mantuano, Elisabetta; Stiles, T; Hicks, D; Gonias, S.. - STAMPA. - (2013), pp. 42-42. ((Intervento presentato al convegno XIVth International Workshop Molecular and Cellular Biology of Plasminogen Activation tenutosi a South Bend/Notre Dame, Indiana, USA nel June 4-8 2013.

Ligand-specific co-receptor recruitment determines the signaling activity of LRP1 in response to tissue-type plasminogen activator and myelin-associated glicoprotein

MANTUANO, ELISABETTA;
2013

Abstract

The LDL receptor-related protein (LRP1) couples ligand endocytosis with cell-signaling; however, the nature of the signaling response varies under specific conditions. Variability in LRP1 signaling is evident in studies of cultured neurons and neuron-like cell lines. Specific LRP1 ligands, including tissue-type plasminogen activator (tPA) and activated α2-macroglobulin, activate ERK and Akt in these cells, promoting neurite outgrowth. Myelin-derived inhibitory proteins, such as Myelin-associated Glycoprotein (MAG), also bind to LRP1; however, MAG-binding to LRP1 activates RhoA and inhibits neurite outgrowth. In this study, we analyzed the LRP1 receptor assembly responsible for ERK activation and compared this with the receptor complex that assembles in response to MAG. We found that in PC12 and N2a cells, activation of ERK by tPA strictly required LRP1. The NMDA receptor and Trk receptors also were necessary for LRP1 signaling to ERK in response to tPA. By contrast, MAG was unique in its ability to recruit p75NTR into association with LRP1. p75NTR has been previously implicated in RhoA activation and inhibition of neuronal regeneration in spinal cord injury. Although tPA and MAG both bind to the clusters of complement-like repeats (CCRs) in LRP1, the binding sites for these two ligands may not be identical. p75NTR co-immunoprecipitated with LRP1 from injured but not uninjured rodent spinal cords in vivo. Regulation of LRP1 signaling represents an important target for therapeutics development in CNS injury.
XIVth International Workshop Molecular and Cellular Biology of Plasminogen Activation
04 Pubblicazione in atti di convegno::04d Abstract in atti di convegno
Ligand-specific co-receptor recruitment determines the signaling activity of LRP1 in response to tissue-type plasminogen activator and myelin-associated glicoprotein / Mantuano, Elisabetta; Stiles, T; Hicks, D; Gonias, S.. - STAMPA. - (2013), pp. 42-42. ((Intervento presentato al convegno XIVth International Workshop Molecular and Cellular Biology of Plasminogen Activation tenutosi a South Bend/Notre Dame, Indiana, USA nel June 4-8 2013.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/769761
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