Advances in slit diaphragm signaling

New, Laura A.; Martín, Claire Emilie; Jones, Nina

doi:10.1097/01.mnh.0000447018.28852.b6

Cited by 37 publications

(35 citation statements)

References 114 publications

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“…Digested cortices were passed through 100-mm sterile nylon cell strainers with chilled PBS to obtain glomeruli. Red blood cells were lysed in sterile Ack lysis buffer (150 mM NH 4 Cl, 10 mM KHCO 3 , and 0.1 mM EDTA), and the remaining enriched glomeruli were lysed in phospholipase C lysis buffer supplemented with fresh protease inhibitors as described above. Lysed glomeruli were further subjected to sonication for 10 s on ice before proceeding to separating soluble protein from the cell pellet through centrifugation.…”

Section: Methodsmentioning

confidence: 99%

“…The extracellular region of nephrin interacts with adjacent nephrin molecules, forming a structural filter, whereas the intracellular tail coordinates signaling cascades that regulate actin dynamics as well as podocyte survival (4). Nephrin is phosphorylated on intracellular tyrosine residues by the Src family kinase (SFK) 4 Fyn, and phosphorylation of three of these tyrosines, in particular Tyr-1176, Tyr-1193, and Tyr-1217, creates docking sites for the Nck1/2 cytoskeletal adaptor proteins (5,6). Nephrin phosphorylation on these sites is reduced in renal diseases associated with podocyte effacement (7,8), and this phosphorylation is essential in mice for stabilization and restoration of foot process morphology (9).…”

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confidence: 99%

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Nephrin Suppresses Hippo Signaling through the Adaptor Proteins Nck and WTIP

Chahi¹,

Martín²,

Jones

2016

Journal of Biological Chemistry

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Podocytes are key components of the kidney blood filtration barrier, and their ability to withstand hemodynamic strain is proposed to be closely tied to their unique and flexible cytoarchitecture. However, the mechanisms that control such mechanotransduction are poorly understood. We have previously established that tyrosine phosphorylation of the transmembrane protein nephrin promotes recruitment of the Nck1/2 cytoskeletal adaptor proteins and downstream actin remodeling. We now reveal that Nck integrates nephrin with the Hippo kinase cascade through association with the adaptor protein WTIP. Using mutational analysis, we show that Nck sequesters WTIP and its binding partner Lats1 to phosphorylated nephrin, resulting in decreased phospho-activation of Lats1. We further demonstrate that, coincident with nephrin dephosphorylation in a transient model of podocyte injury in mice, Lats1 is rapidly activated, and this precedes significant down-regulation of the transcription regulator Yap. Moreover, we show reduced levels of Yap protein in mice with chronic disruption of nephrin phospho-signaling. Together, these findings support the existence of a dynamic molecular link between nephrin signaling and the canonical Hippo pathway in podocytes, which may facilitate the conversion of mechanical cues to biochemical signals promoting podocyte viability.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Nephrin Suppresses Hippo Signaling through the Adaptor Proteins Nck and WTIP

Chahi¹,

Martín²,

Jones

2016

Journal of Biological Chemistry

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“…Within this segment, there exists a number of highly conserved tyrosine (Y) residues ( Table 1) that, on phosphorylation by Fyn kinase, [7][8][9] serve as docking sites for intracellular signaling proteins ( Figure 1A). 10 Through recruitment of actin adaptors, such as p85/PI3K, 11,12 the Cas/Crk complex, 13 and Nck1/2, 8,9,14 nephrin phosphorylation is postulated to facilitate direct and dynamic connection to the podocyte cytoskeleton. Moreover, Nck enhances nephrin phosphorylation via activation of Fyn, 15 and loss of Nck within podocytes leads to reduced nephrin tyrosine phosphorylation and widespread foot process effacement, 15,16 inferring a reciprocal relationship between Nck and nephrin in the maintenance of podocyte structure.…”

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confidence: 99%

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

New¹,

Martín²,

Scott

et al. 2016

JASN

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Podocytes are specialized epithelial cells of the kidney blood filtration barrier that contribute to permselectivity via a series of interdigitating actin-rich foot processes. Positioned between adjacent projections is a unique cell junction known as the slit diaphragm, which is physically connected to the actin cytoskeleton via the transmembrane protein nephrin. Evidence indicates that tyrosine phosphorylation of the intracellular tail of nephrin initiates signaling events, including recruitment of cytoplasmic adaptor proteins Nck1 and Nck2 that regulate actin cytoskeletal dynamics. Nephrin tyrosine phosphorylation is altered in human and experimental renal diseases characterized by pathologic foot process remodeling, prompting the hypothesis that phosphonephrin signaling directly influences podocyte morphology. To explore this possibility, we generated and analyzed knockin mice with mutations that disrupt nephrin tyrosine phosphorylation and Nck1/2 binding (nephrin Y3F/Y3F mice). Homozygous nephrin Y3F/Y3F mice developed progressive proteinuria accompanied by structural changes in the filtration barrier, including podocyte foot process effacement, irregular thickening of the glomerular basement membrane, and dilated capillary loops, with a similar but later onset phenotype in heterozygous animals. Furthermore, compared with wild-type mice, nephrin Y3F/Y3F mice displayed delayed recovery in podocyte injury models. Profiling of nephrin tyrosine phosphorylation dynamics in wild-type mice subjected to podocyte injury indicated site-specific differences in phosphorylation at baseline, injury, and recovery, which correlated with loss of nephrin-Nck1/2 association during foot process effacement. Our results define an essential requirement for nephrin tyrosine phosphorylation in stabilizing podocyte morphology and suggest a model in which dynamic changes in phosphotyrosine-based signaling confer plasticity to the podocyte actin cytoskeleton.

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“…Besides the important role in scaffolding of SD, Nephrin also serves as a "signaling node" in the SD by transmitting extracellular domain from the SD to the intracellular actin cytoskeleton [27,49,50]. Nephrin has the nine tyrosine residues in the intracellular domain, some of which are phosphorylated after ligand binding [51] and could serve as docking sites for SH2 domain-containing kinase and adaptor proteins.…”

Section: Nephrin-mediated Intracellular Signaling Pathwaysmentioning

confidence: 99%

An update: the role of Nephrin inside and outside the kidney

2015

Sci. China Life Sci.

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Nephrin is a key molecule in podocytes to maintain normal slit diaphragm structure. Nephin interacts with many other podocyte and slit diaphragm protein and also mediates important cell signaling pathways in podocytes. Loss of nephrin during the development leads to the congenital nephrotic syndrome in children. Reduction of nephrin expression is often observed in adult kidney diseases including diabetic nephropathy and HIV-associated nephropathy. The critical role of nephrin has been confirmed by different animal models with nephrin knockout and knockdown. Recent studies demonstrate that knockdown of nephrin expression in adult mice aggravates the progression of unilateral nephrectomy and Adriamycin-induced kidney disease. In addition to its critical role in maintaining normal glomerular filtration unit in the kidney, nephrin is also expressed in other organs. However, the exact role of nephrin in kidney and extra-renal organs has not been well characterized. Future studies are required to determine whether nephrin could be developed as a drug target to treat patients with kidney disease.

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Advances in slit diaphragm signaling

Cited by 37 publications

References 114 publications

Nephrin Suppresses Hippo Signaling through the Adaptor Proteins Nck and WTIP

Nephrin Suppresses Hippo Signaling through the Adaptor Proteins Nck and WTIP

Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture

An update: the role of Nephrin inside and outside the kidney

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