Non‐proteolytic neurotrophic effects of tissue plasminogen activator on cultured mouse cerebrocortical neurons

Lee, Heeyoung; Hwang, In-Sun; Im, Hana; Koh, Jae‐Young; Kim, Yang‐Hee

doi:10.1111/j.1471-4159.2007.04417.x

Cited by 38 publications

(35 citation statements)

References 53 publications

(131 reference statements)

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“…LRP-1-mediated Erk activation by tPA has been reported in various cellular systems 13,33,35 ; however, the exact mechanism has not been fully understood. Tyrosine residues on the ␤ subunit of LRP-1 provide docking sites for signaling adaptor protein including Shc, 22,39,40 which on phosphorylation will then recruit Grb2-Sos, potentiating activation of Ras.…”

Section: Discussionmentioning

confidence: 99%

tPA Activates LDL Receptor-Related Protein 1-Mediated Mitogenic Signaling Involving the p90RSK and GSK3β Pathway

Lin

Mars

et al. 2010

The American Journal of Pathology

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In renal fibrosis , interstitial fibroblasts have an increased proliferative phenotype , and the numbers of interstitial fibroblasts closely correlate with the extent of kidney damage. The mechanisms underlying proliferation and resulting expansion of the interstitium remain largely unknown. Here we define the intracellular signaling events by which tissue plasminogen activator (tPA) promotes renal interstitial fibroblast proliferation. tPA promoted the proliferation of renal interstitial fibroblasts independent of its protease activity. The mitogenic effect of tPA required Tyr 4507 phosphorylation of the cytoplasmic tail of its receptor LDL receptor-related protein 1. tPA triggered sequential proliferative signaling events involving Erk1/2 , p90RSK , GSK3␤ phosphorylation , and cyclin D1 induction. Blockade of Erk1/2 activation or knockdown of p90RSK suppressed tPA-induced GSK3␤ phosphorylation, cyclin D1 expression, and fibroblast proliferation. In contrast, expression of constitutively active Mek1 mimicked tPA in inducing GSK3␤ phosphorylation and cyclin D1 expression. Ectopic overexpression of an uninhibitable GSK3␤ mutant eliminated tPA-induced cyclin D1 expression. In the murine obstruction model , tPA deficiency reduced renal GSK3␤ phosphorylation and induction of PCNA and FSP-1. These findings show that tPA induces Tyr 4507 phosphorylation of LDL receptor-related protein 1 , which in turn leads to the downstream phosphorylation of Erk1/2 , p90RSK , and GSK3␤, followed by the induction of cyclin D1 in murine interstitial fibroblasts. This study implicates tPA as a mitogen that promotes interstitial fibroblast proliferation , leading to expansion of these cells. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

tPA Activates LDL Receptor-Related Protein 1-Mediated Mitogenic Signaling Involving the p90RSK and GSK3β Pathway

Lin

Mars

et al. 2010

The American Journal of Pathology

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“…Therefore, tPA is Recent findings have defined tPA as a hybrid molecule with protease and cytokine functions. [12][13][14][15]19,[28][29][30][31][32][33][34][35] As a member of the serine protease family, tPA also activates numerous growth factors, including TGF-b1 and platelet-derived growth factor CC, [9][10][11] in addition to its ability to activate numerous zymogens into active enzymes that are involved in fibrinolysis and extracellular matrix degradation. In the present study, we determined that tPA-induced activation of the NF-kB pathway is independent of its protease activity, because the mutant nonenzymatic tPA, in which the serine within the active site of the enzyme was replaced with alanine, 27 also induced NF-kB activation in a dose-dependent manner (Figure 2A).…”

Section: Discussionmentioning

confidence: 99%

Tissue Plasminogen Activator Activates NF-κB through a Pathway Involving Annexin A2/CD11b and Integrin-Linked Kinase

Lin

2012

Journal of the American Society of Nephrology

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NF-kB activation is central to the initiation and progression of inflammation, which contributes to the pathogenesis of CKD. Tissue plasminogen activator (tPA) modulates the NF-kB pathway, but the underlying mechanism remains unknown. We investigated the role of tPA signaling in macrophage NF-kB activation and found that tPA activated NF-kB in a time-and dose-dependent manner. tPA also induced the expression of the NF-kB-dependent chemokines IP-10 and MIP-1a. The protease-independent action of tPA required its membrane receptor, annexin A2. tPA induced the aggregation and interaction of annexin A2 with integrin CD11b, and ablation of CD11b or administration of anti-CD11b neutralizing antibody abolished the effect of tPA. Knockdown of the downstream effector of CD11b, integrin-linked kinase, or disruption of its engagement with CD11b also blocked tPA-induced NF-kB signaling. In vivo, tPA-knockout mice had reduced NF-kB signaling, fewer renal macrophages, and less collagen deposition than their counterparts. Taken together, these data suggest that tPA activates the NF-kB pathway in macrophages through a signaling pathway involving annexin A2/CD11b-mediated integrin-linked kinase.

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“…[1][2][3] However, tPA not only activates plasminogen, but rather acts through several modalities 4 by interacting with the low-density lipoproteinrelated receptor protein (LRP), [5][6][7][8] annexin-II 9 or N-methyl-Daspartate receptors (NMDAR). 1,[10][11][12] These interactions mediate several potentially damaging effects of tPA, including potentiation of NMDAR-mediated signalling and excitotoxicity.…”

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confidence: 99%

NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity

et al. 2009

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Although the molecular bases of its actions remain debated, tissue-type plasminogen activator (tPA) is a paradoxical brain protease, as it favours some learning/memory processes, but increases excitotoxic neuronal death. Here, we show that, in cultured cortical neurons, tPA selectively promotes NR2D-containing N-methyl-D-aspartate receptor (NMDAR)-dependent activation. We show that tPA-mediated signalling and neurotoxicity through the NMDAR are blocked by co-application of an NR2D antagonist (phenanthrene derivative (2S*, 3R*)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid, PPDA) or knockdown of neuronal NR2D expression. In sharp contrast with cortical neurons, hippocampal neurons do not exhibit NR2D both in vitro and in vivo and are consequently resistant to tPA-promoted NMDAR-mediated neurotoxicity. Moreover, we have shown that activation of synaptic NMDAR prevents further tPA-dependent NMDAR-mediated neurotoxicity and sensitivity to PPDA. This study shows that the earlier described pro-neurotoxic effect of tPA is mediated by NR2D-containing NMDARdependent extracellular signal-regulated kinase activation, a deleterious effect prevented by synaptic pre-activation.

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Non‐proteolytic neurotrophic effects of tissue plasminogen activator on cultured mouse cerebrocortical neurons

Cited by 38 publications

References 53 publications

tPA Activates LDL Receptor-Related Protein 1-Mediated Mitogenic Signaling Involving the p90RSK and GSK3β Pathway

tPA Activates LDL Receptor-Related Protein 1-Mediated Mitogenic Signaling Involving the p90RSK and GSK3β Pathway

Tissue Plasminogen Activator Activates NF-κB through a Pathway Involving Annexin A2/CD11b and Integrin-Linked Kinase

NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity

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