ArticleJournal of the American Society of Nephrology : JASN2009
TbetaRI independently activates Smad- and CD2AP-dependent pathways in podocytes.
Article in Journal of the American Society of Nephrology : JASN, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 40 citations in OpenAlex.
- MicroRNA-21 in glomerular injury.Journal of the American Society of Nephrology : JASN · 2015Trial
- A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes.Cells · 2022Article
- Podocyte-specific deletion of miR-146a increases podocyte injury and diabetic kidney disease.Frontiers in medicine · 2022Article
- Renal cell markers: lighthouses for managing renal diseases.American journal of physiology. Renal physiology · 2021Article
- Wubeizi Ointment Suppresses Keloid Formation through Modulation of the mTOR Pathway.BioMed research international · 2020Article
- Tyrosine Phosphorylation of CD2AP Affects Stability of the Slit Diaphragm Complex.Journal of the American Society of Nephrology : JASN · 2019Article
- Conditional knockout of TGF-βRII /Smad2 signals protects against acute renal injury by alleviating cell necroptosis, apoptosis and inflammation.Theranostics · 2019Article
- The Role of Trio, a Rho Guanine Nucleotide Exchange Factor, in Glomerular Podocytes.International journal of molecular sciences · 2018Article
- Transforming growth factor-β1 and phosphatases modulate COX-2 protein expression and TAU phosphorylation in cultured immortalized podocytes.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2018Article
- Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis.Scientific reports · 2017Article
- Expression of TGF-β1/mTOR signaling pathway in pathological scar fibroblasts.Molecular medicine reports · 2017Article
- Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1.The Journal of biological chemistry · 2017Article
- Triptolide protects podocytes from TGF-β-induced injury by preventing miR-30 downregulation.American journal of translational research · 2017Article
- Transforming Growth Factor β1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis.The Journal of biological chemistry · 2015Article
- Pentoxifylline Attenuates Proteinuria in Anti-Thy1 Glomerulonephritis via Downregulation of Nuclear Factor-κB and Smad2/3 Signaling.Molecular medicine (Cambridge, Mass.) · 2015Article
- Qiwei granules alleviates podocyte lesion in kidney of diabetic KK-Ay mice.BMC complementary and alternative medicine · 2015Article
- Astragaloside effect on TGF-β1, SMAD2/3, and α-SMA expression in the kidney tissues of diabetic KKAy mice.International journal of clinical and experimental pathology · 2015Article
- Article
- Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro.American journal of physiology. Renal physiology · 2014Article
- Molecular basis of etiological implications in Alzheimer's disease: focus on neuroinflammation.Molecular neurobiology · 2013Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
TGF-beta regulates differentiation, growth, and apoptosis of podocytes and mediates podocyte depletion in glomerulosclerosis. TGF-beta promotes proapoptotic signaling mediated by Smad3 but also activates prosurvival pathways such as phosphoinositide-3 kinase (PI3K)/AKT; the latter requires the CD2-associated adaptor protein (CD2AP) in podocytes. Whether the opposing activities mediated by Smad proteins and CD2AP involve molecular cross-talk is unknown. Here, we report that CD2AP-dependent early activation of the antiapoptotic PI3K/AKT pathway does not require TGF-beta receptor-regulated Smad2 and Smad3. We found that the C-terminal region of CD2AP interacts directly with the cytoplasmic tail of the TGF-beta receptor type I (TbetaRI) in a kinase-dependent manner and that the interaction between the TbetaRI and the p85 subunit of PI3K requires CD2AP. Consistent with the proapoptotic function of Smad signaling, Smad2/3-deficient podocytes were hyperproliferative and resistant to TGF-beta-induced growth inhibition and apoptosis. In contrast, CD2AP-deficient cells were hypoproliferative and hypersensitive to TGF-beta-induced apoptosis. In vivo, to determine the effects of reduced Smad3 or CD2AP gene dosage on podocyte apoptosis and proteinuria characteristic of TGF-beta1 transgenic mice, we generated TGF-beta1 transgenic mice deficient for Smad3 or heterozygous for CD2AP. Smad3 deficiency ameliorated podocyte apoptosis, and CD2AP heterozygosity increased both podocyte apoptosis and proteinuria. These data define distinct canonical (Smad) and noncanonical (CD2AP/PI3K/AKT) pathways that arise from direct, independent interactions with the TbetaRI and that mediate opposing signals for podocyte death or survival.
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Registered trials
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 Socratic graph.