ArticleKidney international2019
Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2.
Article in Kidney international, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 citations in OpenAlex.
- The Molecular Machinery of Synaptic Plasticity and Its Potential Role in the Aetiology of Schizophrenia.Molecular neurobiology · 2026Review
- Article
- Emerging genetic mechanisms of glomerular proteinuria: a podocyte-centered multi-layer network perspective.Frontiers in genetics · 2026Review
- Integrating machine learning and GWAS for variant prioritization in the INCIPE cohort highlights ABC transporter genes in chronic kidney disease.Frontiers in genetics · 2026Article
- HomozygousRenal failure · 2025Article
- Podocytes in health and disease: from development to regeneration.Human cell · 2025Review
- Reduced nephrin tyrosine phosphorylation impairs podocyte force transmission and accelerates detachment in disease.iScience · 2025Article
- Revisiting nephrin signaling and its specialized effects on the uniquely adaptable podocyte.The Biochemical journal · 2025Review
- When should the nephrologist think about genetics in patients with glomerular diseases?Clinical kidney journal · 2025Review
- Celastrol protects against diabetic nephropathy by modulating immune-related pathways: a bioinformatics and experimental validation.American journal of translational research · 2025Article
- Identification and validation of biomarkers in membranous nephropathy and pan-cancer analysis.Frontiers in immunology · 2024Article
- Huangqi decoction ameliorates kidney injury in db/db mice by regulating the BMP/Smad signaling pathway.BMC complementary medicine and therapies · 2023Article
- Phosphorylation-dependent recognition of diverse protein targets by the cryptic GK domain of MAGI MAGUKs.Science advances · 2023Article
- Rap1 Activity Is Essential for Focal Adhesion and Slit Diaphragm Integrity.Frontiers in cell and developmental biology · 2022Article
- circ‑Grm1 promotes pulmonary artery smooth muscle cell proliferation and migration via suppression of GRM1 expression by FUS.International journal of molecular medicine · 2021Article
- Review
- DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation.American journal of human genetics · 2020Article
- Podocyte RhoGTPases: new therapeutic targets for nephrotic syndrome?F1000Research · 2019Review
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Authors and funding
17 authors at 9 institutions in 3 countries.
Funding
Abstract
The essential role of membrane associated guanylate kinase 2 (MAGI2) in podocytes is indicated by the phenotypes of severe glomerulosclerosis of both MAGI2 knockout mice and in patients with congenital nephrotic syndrome (CNS) caused by mutations in MAGI2. Here, we show that MAGI2 forms a complex with the Rap1 guanine nucleotide exchange factor, RapGEF2, and that this complex is lost when expressing MAGI2 CNS variants. Co-expression of RapGEF2 with wild-type MAGI2, but not MAGI2 CNS variants, enhanced activation of the small GTPase Rap1, a central signaling node in podocytes. In mice, podocyte-specific RapGEF2 deletion resulted in spontaneous glomerulosclerosis, with qualitative glomerular features comparable to MAGI2 knockout mice. Knockdown of RapGEF2 or MAGI2 in human podocytes caused similar reductions in levels of Rap1 activation and Rap1-mediated downstream signaling. Furthermore, human podocytes expressing MAGI2 CNS variants show severe abnormalities of cellular morphology and dramatic loss of actin cytoskeletal organization, features completely rescued by pharmacological activation of Rap1 via a non-MAGI2 dependent upstream pathway. Finally, immunostaining of kidney sections from patients with congenital nephrotic syndrome and MAGI2 mutations showed reduced podocyte Rap1-mediated signaling. Thus, MAGI2-RapGEF2-Rap1 signaling is essential for normal podocyte function. Hence, disruption of this pathway is an important cause of the renal phenotype induced by MAGI2 CNS mutations.
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