Fyn Binds to and Phosphorylates the Kidney Slit Diaphragm Component Nephrin

Verma, Rakesh; Wharram, Bryan L.; Kovari, Iulia A.; Kunkel, Robin G.; Nihalani, Deepak; Wary, Kishore K.; Wiggins, Roger C.; Killen, Paul D.; Holzman, Lawrence B.

doi:10.1074/jbc.m301689200

Cited by 212 publications

(278 citation statements)

References 30 publications

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“…According to this analysis, nephrin may be phosphorylated in tyrosine residues by Fyn, Src, and Yes (Supplemental Fig. 1), as already published (Verma et al, 2003(Verma et al, , 2006Quack et al, 2006), as well as by ABL1, whereas b-adducin appears phosphorylated by Fyn, as known (Gotoh et al, 2006), as well as by Yes (Supplemental Fig. 2).…”

Section: Effect Of Rostafuroxin On Sh2-domain Interactionsmentioning

confidence: 54%

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Ferrandi

Molinari

Rastaldi

et al. 2014

J Pharmacol Exp Ther

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Glomerulopathies are important causes of morbidity and mortality. Selective therapies that address the underlying mechanisms are still lacking. Recently, two mechanisms, mutant b-adducin and ouabain, have been found to be involved in glomerular podocytopathies and proteinuria through nephrin downregulation. The main purpose of the present study was to investigate whether rostafuroxin, a novel antihypertensive agent developed as a selective inhibitor of Src-SH2 interaction with mutant adducinand ouabain-activated Na,K-ATPase, may protect podocytes from adducin-and ouabain-induced effects, thus representing a novel pharmacologic approach for the therapy of podocytopathies and proteinuria caused by the aforementioned mechanisms. To study the effect of rostafuroxin on podocyte protein changes and proteinuria, mice carrying mutant b-adducin and ouabain hypertensive rats were orally treated with 100 mg/kg per day rostafuroxin. Primary podocytes from congenic rats carrying mutant a-adducin or b-adducin (NB) from Milan hypertensive rats and normal rat podocytes incubated with 10 29 M ouabain were cultured with 10 29 M rostafuroxin. The results indicated that mutant b-adducin and ouabain caused podocyte nephrin loss and proteinuria in animal models. These alterations were reproduced in primary podocytes from NB rats and normal rats incubated with ouabain. Treatment of animals, or incubation of cultured podocytes with rostafuroxin, reverted mutant b-adducin-and ouabain-induced effects on nephrin protein expression and proteinuria. We conclude that rostafuroxin prevented podocyte lesions and proteinuria due to mutant b-adducin and ouabain in animal models. This suggests a potential therapeutic effect of rostafuroxin in patients with glomerular disease progression associated with these two mechanisms.

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Section: Effect Of Rostafuroxin On Sh2-domain Interactionsmentioning

confidence: 54%

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Ferrandi

Molinari

Rastaldi

et al. 2014

J Pharmacol Exp Ther

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“…Nephrin, together with podocin, stimulates the AP-1 transcription factor via activation of mitogen-activated protein kinases, 57 associates with the p85 regulatory subunit of phosphoinositide 3-OH kinase (PI3K), stimulates PI3K-dependent AKT signaling in podocytes, 58 and is phosphorylated by Fyn, a Src family kinase. 36 The events that trigger these effects and the functional consequences remain to be worked out.…”

Section: Discussionmentioning

confidence: 99%

“…36 To determine whether rat nephrin is phosphorylated when expressed in MDCK cells, we digested cell lysates with alkaline phosphatase. This treatment resulted in a shift in the electrophoretic mobility of nephrin from ϳ180 to 185 to ϳ160 to 170 kd ( Figure 1D).…”

Section: Nephrin Is N-glycosylated and Phosphorylated In Mdck-nephrinmentioning

confidence: 99%

Nephrin Forms a Complex with Adherens Junction Proteins and CASK in Podocytes and in Madin-Darby Canine Kidney Cells Expressing Nephrin

Lehtonen

Kudlicka

Holthöfer

et al. 2004

The American Journal of Pathology

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“…Nephrin is phosphorylated by an Src family kinase, Fyn, and stimulates the AP-1 transcription factor through activation of mitogen-activated protein kinases. 45,56 Nephrin also associates with p85 regulatory subunit of PI3K and stimulates PI3K-dependent AKT signaling in podocytes. 46 In polarized epithelial cells, MAGI-1 interacts with several signaling molecules including RapGEP, b-catenin and mNET1.…”

Section: Magi-1 Interacts With Nephrin S Hirabayashi Et Almentioning

confidence: 99%

MAGI-1 is a component of the glomerular slit diaphragm that is tightly associated with nephrin

Hirabayashi

Mori

Kansaku

et al. 2005

Laboratory Investigation

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MAGUK with inverted domain structure-1 (MAGI-1) is a membrane-associated protein with one guanylate kinase, six PSD-95/Dlg-A/ZO-1 (PDZ), and two WW domains and is localized at tight junctions in epithelial cells. MAGI-1 interacts with various proteins and is proposed to function as a scaffold protein. In the previous study, we discovered a MAGI-1-interacting cell adhesion molecule junctional adhesion molecule 4 (JAM4). Both proteins are highly expressed in glomerular podocytes in the kidney and partially colocalized. In this study, we have further searched for a binding partner of MAGI-1 in the kidney through yeast two-hybrid screening and obtained nephrin. Nephrin is a cell adhesion molecule specifically localized at the slit diaphragm between neighboring foot processes of podocytes. Biochemical studies reveal that nephrin directly binds to the middle PDZ domains of MAGI-1 through its carboxyl terminus but does not bind to ZO-1. MAGI-1 forms a tripartite complex with nephrin and JAM4 in vitro. Immunoelectron microscopy shows that the localization of MAGI-1 is restricted to the slit diaphragm, whereas JAM4 is also distributed on apical membranes of podocytes. In puromycin aminonucleoside-induced nephrotic podocytes, MAGI-1 is localized with nephrin at the displaced slit diaphragm. These data indicate that MAGI-1 is a component of the slit diaphragm and tightly interacts with nephrin and JAM4 in vivo. MAGI-1 may play a role in determining the boundary between the apical and the bosolateral domain at the level of slit diaphragm. Laboratory Investigation (2005) 85, 1528-1543.

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Fyn Binds to and Phosphorylates the Kidney Slit Diaphragm Component Nephrin

Cited by 212 publications

References 30 publications

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Nephrin Forms a Complex with Adherens Junction Proteins and CASK in Podocytes and in Madin-Darby Canine Kidney Cells Expressing Nephrin

MAGI-1 is a component of the glomerular slit diaphragm that is tightly associated with nephrin

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