ArticleThe American journal of pathology2010
tPA activates LDL receptor-related protein 1-mediated mitogenic signaling involving the p90RSK and GSK3beta pathway.
Article in The American journal of pathology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 32 citations in OpenAlex.
- p90RSK modulates inter-and intracellular signaling in kidney diseases.Frontiers in cell and developmental biology · 2025Review
- Macrophage Function Modulated by tPA Signaling in Mouse Experimental Kidney Disease Models.International journal of molecular sciences · 2023Review
- Overexpression of Neuron-Derived Orphan Receptor 1 (NOR-1) Rescues Cardiomyocytes from Cell Death and Improves Viability after Doxorubicin Induced Stress.Biomedicines · 2021Article
- Endocytic Protein Defects in the Neural Crest Cell Lineage and Its Pathway Are Associated with Congenital Heart Defects.International journal of molecular sciences · 2021Review
- Cell Cycle Dysregulation and Renal Fibrosis.Frontiers in cell and developmental biology · 2021Review
- Review
- Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Is a Negative Regulator of Oligodendrocyte Progenitor Cell Differentiation in the Adult Mouse Brain.Frontiers in cell and developmental biology · 2020Article
- The Ser/Thr kinase p90RSK promotes kidney fibrosis by modulating fibroblast-epithelial crosstalk.The Journal of biological chemistry · 2019Article
- Role of p90RSK in Kidney and Other Diseases.International journal of molecular sciences · 2019Review
- Inhibition of Lung Tumor Development in ApoE Knockout Mice via Enhancement of TREM-1 Dependent NK Cell Cytotoxicity.Frontiers in immunology · 2019Article
- Low Density Lipoprotein Receptor-Related Protein-1 in Cardiac Inflammation and Infarct Healing.Frontiers in cardiovascular medicine · 2019Review
- Tissue-type plasminogen activator modulates macrophage M2 to M1 phenotypic change through annexin A2-mediated NF-κB pathway.Oncotarget · 2017Article
- The pleiotropic effects of tissue plasminogen activator in the brain: implications for stroke recovery.Neural regeneration research · 2016Article
- Tissue-type plasminogen activator (tPA) promotes M1 macrophage survival through p90 ribosomal S6 kinase (RSK) and p38 mitogen-activated protein kinase (MAPK) pathway.The Journal of biological chemistry · 2015Article
- Activation of glycogen synthase kinase 3β ameliorates diabetes-induced kidney injury.The Journal of biological chemistry · 2014Article
- LRP-1: functions, signaling and implications in kidney and other diseases.International journal of molecular sciences · 2014Review
- Myeloid-derived tissue-type plasminogen activator promotes macrophage motility through FAK, Rac1, and NF-κB pathways.The American journal of pathology · 2014Article
- Tissue Plasminogen Activator: Side Effects and Signaling.Journal of drug design and research · 2014Article
- tPA regulates neurite outgrowth by phosphorylation of LRP5/6 in neural progenitor cells.Molecular neurobiology · 2014Article
- Tissue plasminogen activator and inflammation: from phenotype to signaling mechanisms.American journal of clinical and experimental immunology · 2014Review
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
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, GSK3β phosphorylation, and cyclin D1 induction. Blockade of Erk1/2 activation or knockdown of p90RSK suppressed tPA-induced GSK3β phosphorylation, cyclin D1 expression, and fibroblast proliferation. In contrast, expression of constitutively active Mek1 mimicked tPA in inducing GSK3β phosphorylation and cyclin D1 expression. Ectopic overexpression of an uninhibitable GSK3β mutant eliminated tPA-induced cyclin D1 expression. In the murine obstruction model, tPA deficiency reduced renal GSK3β 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 GSK3β, 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.