Nephrin Signaling Results in Integrin β1 Activation

Dlugos, C. P.; Picciotto, Cara; Lepa, Carolin; Krakow, Malte; Stöber, Antje; Eddy, Mee-Ling; Weide, Thomas; Jeibmann, Astrid; Krahn, Michael P.; Marck, Veerle Van; Klingauf, Jürgen; Ricker, Andrea; Wedlich‐Söldner, Roland; Pavenstädt, Hermann; Klämbt, Christian; George, Britta

doi:10.1681/asn.2018040362

Cited by 26 publications

(33 citation statements)

References 65 publications

(135 reference statements)

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“…A recent study demonstrated that nephrin signaling results in integrin β1 activation. The finding implied that nephrin-mediated signal regulates podocyte attachment to glomerular basement membrane [98].…”

Section: Slit Diaphragm Functions As a Signaling Platformmentioning

confidence: 90%

New insight into podocyte slit diaphragm, a therapeutic target of proteinuria

Kawachi

Fukusumi

2020

Clin Exp Nephrol

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Dysfunction of slit diaphragm, a cell–cell junction of glomerular podocytes, is involved in the development of proteinuria in several glomerular diseases. Slit diaphragm should be a target of a novel therapy for proteinuria. Nephrin, NEPH1, P-cadherin, FAT, and ephrin-B1 were reported to be extracellular components forming a molecular sieve of the slit diaphragm. Several cytoplasmic proteins such as ZO-1, podocin, CD2AP, MAGI proteins and Par-complex molecules were identified as scaffold proteins linking the slit diaphragm to the cytoskeleton. In this article, new insights into these molecules and the pathogenic roles of the dysfunction of these molecules were introduced. The slit diaphragm functions not only as a barrier but also as a signaling platform transfer the signal to the inside of the cell. For maintaining the slit diaphragm function properly, the phosphorylation level of nephrin is strictly regulated. The recent studies on the signaling pathway from nephrin, NEPH1, and ephrin-B1 were reviewed. Although the mechanism regulating the function of the slit diaphragm had remained unclear, recent studies revealed TRPC6 and angiotensin II-regulating mechanisms play a critical role in regulating the barrier function of the slit diaphragm. In this review, recent investigations on the regulation of the slit diaphragm function were reviewed, and a strategy for the establishment of a novel therapy for proteinuria was proposed.

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Section: Slit Diaphragm Functions As a Signaling Platformmentioning

confidence: 90%

New insight into podocyte slit diaphragm, a therapeutic target of proteinuria

Kawachi

Fukusumi

2020

Clin Exp Nephrol

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“…Importantly, intracellular actin accumulation quantitatively correlated with perturbed distribution of nephrin in the plasma membrane of fly nephrocytes, which is reminiscent of other nephropathy models in fly. 46 This defect could be linked to a function of cortical actin in the organization of the slit diaphragm 47 or owing to defects in trafficking. The latter notion is supported by our findings on the cessation of organelle mobility during the CaAR reaction 4 and on expression of active INF2 variants.…”

Section: Discussionmentioning

confidence: 99%

A Deregulated Stress Response Underlies Distinct INF2-Associated Disease Profiles

Bayraktar

Nehrig

Menis

et al. 2020

JASN

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BackgroundMonogenic diseases provide favorable opportunities to elucidate the molecular mechanisms of disease progression and improve medical diagnostics. However, the complex interplay between genetic and environmental factors in disease etiologies makes it difficult to discern the mechanistic links between different alleles of a single locus and their associated pathophysiologies. Inverted formin 2 (INF2), an actin regulator, mediates a stress response—calcium mediated actin reset, or CaAR—that reorganizes the actin cytoskeleton of mammalian cells in response to calcium influx. It has been linked to the podocytic kidney disease focal segemental glomerulosclerosis (FSGS), as well as to cases of the neurologic disorder Charcot–Marie–Tooth disease that are accompanied by nephropathy, mostly FSGS.MethodsWe used a combination of quantitative live cell imaging and validation in primary patient cells and Drosophila nephrocytes to systematically characterize a large panel of >50 autosomal dominant INF2 mutants that have been reported to cause either FSGS alone or with Charcot–Marie–Tooth disease.ResultsWe found that INF2 mutations lead to deregulated activation of formin and a constitutive stress response in cultured cells, primary patient cells, and Drosophila nephrocytes. We were able to clearly distinguish between INF2 mutations that were linked exclusively to FSGS from those that caused a combination of FSGS and Charcot–Marie–Tooth disease. Furthermore, we were able to identify distinct subsets of INF2 variants that exhibit varying degrees of activation.ConclusionsOur results suggest that CaAR can be used as a sensitive assay for INF2 function and for robust evaluation of diseased-linked variants of formin. More broadly, these findings indicate that cellular profiling of disease-associated mutations has potential to contribute substantially to sequence-based phenotype predictions.

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“…This phenotype is reminiscent of other nephropathy models in fly nephrocytes, such as nephrotic syndrome 28 . The defect in nephrin distribution could either be directly linked to a function of cortical actin in the organization of the slit diaphragm 29 or be due to defects in nephrin trafficking. The latter notion is supported by our findings on the cessation of organelle mobility, which occurs transiently during the CaAR reaction 4…”

Section: Discussionmentioning

confidence: 99%

A deregulated stress response underlies distinct INF2 associated disease profiles

Bayraktar

Nehrig

Menis

et al. 2019

Preprint

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Monogenic diseases provide favorable opportunities to elucidate the molecular mechanisms of disease progression and improve medical diagnostics. However, the complex interplay between genetic and environmental factors in disease etiologies makes it difficult to discern the mechanistic links between different alleles of a single locus and their associated pathophysiologies. Here we systematically characterize a large panel (>50) of autosomal dominant mutants of the actin regulator inverted formin 2 (INF2) that have been reported to cause the podocytic kidney disease focal segmental glomerulosclerosis (FSGS) and the neurological disorder Charcot Marie-Tooth disease (CMT). We found that INF2 mutations lead to deregulated activation of the formin and a constitutive stress response in cultured cells, primary patient cells and Drosophila nephrocytes.Using quantitative live-cell imaging we were able to identify distinct subsets of INF2 variants that exhibit varying degrees of activation. Furthermore, we could clearly distinguish between INF2 mutations that were linked exclusively to FSGS from those that caused a combination of FSGS and CMT. Our results indicate that cellular profiling of disease-associated mutations can contribute substantially to sequence-based phenotype predictions.

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Nephrin Signaling Results in Integrin β1 Activation

Cited by 26 publications

References 65 publications

New insight into podocyte slit diaphragm, a therapeutic target of proteinuria

New insight into podocyte slit diaphragm, a therapeutic target of proteinuria

A Deregulated Stress Response Underlies Distinct INF2-Associated Disease Profiles

A deregulated stress response underlies distinct INF2 associated disease profiles

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