Nephrin Suppresses Hippo Signaling through the Adaptor Proteins Nck and WTIP

Chahi, Ava Keyvani; Martín, Claire Emilie; Jones, Nina

doi:10.1074/jbc.m116.724245

Cited by 18 publications

(22 citation statements)

References 31 publications

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“…To examine this, we employed a mouse model of reversible podocyte injury caused by injection of nephrotoxic serum (NTS), which correlates with transient permeability of the glomerular filtration barrier ( proteinuria) and nephrin endocytosis (Haase et al, 2017;Königshausen et al, 2016). As we have reported previously (Keyvani Chahi et al, 2016), proteinuria peaked at 24 h post-NTS injection (Fig. 7A), although it could be detected as early as 6 h post-NTS injection (Fig.…”

Section: Hyperphosphorylation Of Nephrin Ydxv Motifs In Vivo Triggerssupporting

confidence: 86%

Multivalent nephrin–Nck interactions define a threshold for clustering and tyrosine-dependent nephrin endocytosis

Martín

New

Phippen

et al. 2020

Journal of Cell Science

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Assembly of signaling molecules into micrometer-sized clusters is driven by multivalent protein-protein interactions, such as those found within the nephrin-Nck (Nck1 or Nck2) complex. Phosphorylation on multiple tyrosine residues within the tail of the nephrin transmembrane receptor induces recruitment of the cytoplasmic adaptor protein Nck, which binds via its triple SH3 domains to various effectors, leading to actin assembly. The physiological consequences of nephrin clustering are not well understood. Here, we demonstrate that nephrin phosphorylation regulates the formation of membrane clusters in podocytes. We also reveal a connection between clustering and endocytosis, which appears to be driven by threshold levels of nephrin tyrosine phosphorylation and Nck SH3 domain signaling. Finally, we expose an in vivo correlation between transient changes in nephrin tyrosine phosphorylation, nephrin localization and integrity of the glomerular filtration barrier during podocyte injury. Altogether, our results suggest that nephrin phosphorylation determines the composition of effector proteins within clusters to dynamically regulate nephrin turnover and podocyte health.

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Section: Hyperphosphorylation Of Nephrin Ydxv Motifs In Vivo Triggerssupporting

confidence: 86%

Multivalent nephrin–Nck interactions define a threshold for clustering and tyrosine-dependent nephrin endocytosis

Martín

New

Phippen

et al. 2020

Journal of Cell Science

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“…Total and phosphorylated nephrin levels were significantly decreased in podocytes after Ang II stimulation; however, c-Abl small interfering RNA (siRNA) and STI571 (c-Abl inhibitor) pretreatment had no influence on total nephrin and phosphorylated nephrin levels 20 . To further investigate the nephrin-c-Abl signaling pathway, the myc-CD16/7-nephrin construct was transfected into podocytes and nephrin phosphorylation was induced following clustering with the CD16 antibody, as reported previously 13 , 21 , 22 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Role of c-Abl and nephrin in podocyte cytoskeletal remodeling induced by angiotensin II

Yang

Zhong

et al. 2018

Cell Death Dis

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Our previous study showed that angiotensin II (Ang II) exposure diminished the interaction between nephrin and c-Abl, then c-Abl mediated SHIP2-Akt pathway in the process of podocyte injury in vivo and vitro. However, the relationship between nephrin and c-Abl was unknown. Recently, various studies showed that nephrin was required for cytoskeletal remodeling in glomerular podocytes. But its specific mechanisms remain incompletely understood. As a nonreceptor tyrosine kinase involved in cytoskeletal regulation, c-Abl may be a candidate of signaling proteins interacting with Src homology 2/3 (SH2/SH3) domains of nephrin. Therefore, it is proposed that c-Abl contributes to nephrin-dependent cytoskeletal remodeling of podocytes. Herein, we observed that nephrin-c-Abl colocalization were suppressed in glomeruli of patients with proteinuria. Next, CD16/7-nephrin and c-Abl vectors were constructed to investigate the nephrin-c-Abl signaling pathway in podocyte actin-cytoskeletal remodeling. The disorganized cytoskeleton stimulated by cytochalasin D in COS7 cells was dramatically restored by co-transfection with phosphorylated CD16/7-nephrin and c-Abl full-length constructs. Further, co-immunoprecipitation showed that phosphorylated CD16/7-nephrin interacted with wild-type c-Abl, but not with SH2/SH3-defective c-Abl. These findings suggest that phosphorylated nephrin is able to recruit c-Abl in a SH2/SH3-dependent manner and detached c-Abl from dephosphorylated nephrin contributes to cytoskeletal remodeling in podocytes.

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“…The role of nephrin signaling during disease has remained an intense area of interest since the discovery of reduced phosphorylation of group B tyrosine residues in instances of human disease and in various disease models. Alterations in phosphorylation of group B tyrosines has been described in minimal change disease (MCD) ( 100 ) and MN ( 101 ) as well as in the PAN ( 76 , 82 ), protamine sulfate ( 54 , 102 ), nephrotoxic serum (NTS) ( 75 , 88 , 103 ), and lipopolysaccharide ( 102 ) rodent injury models and type I diabetic Akita mice ( 74 , 98 ). Similarly, altered levels of several phosphatases known to influence nephrin’s phospho-status have also been identified in instances of disease ( 104 ).…”

Section: Disruption Of Nephrin Tyrosine Phosphorylation In Podocyte-bmentioning

confidence: 99%

“…It was recently revealed that nephrin signaling directly modulates Hippo mechano-signaling by regulating the stability of its pro-survival component YAP. Phosphorylated nephrin can recruit and sequester Lats2, its negative regulator, at group B tyrosines through an indirect mechanism involving Nck and WTIP ( 103 ), thereby limiting YAP’s degradation. During the initiation of NTS disease in mice, a reduction in nephrin tyrosine phosphorylation is observed at group B residues, reducing Lats2 inhibition, which ultimately leads to YAP’s degradation ( 103 ).…”

Section: Emerging Evidence Of Sd-gbm Communication In Response To Mecmentioning

confidence: 99%

“…Phosphorylated nephrin can recruit and sequester Lats2, its negative regulator, at group B tyrosines through an indirect mechanism involving Nck and WTIP ( 103 ), thereby limiting YAP’s degradation. During the initiation of NTS disease in mice, a reduction in nephrin tyrosine phosphorylation is observed at group B residues, reducing Lats2 inhibition, which ultimately leads to YAP’s degradation ( 103 ). Such activation of Hippo signaling has also been shown to induce podocyte cell death ( 128 ).…”

Section: Emerging Evidence Of Sd-gbm Communication In Response To Mecmentioning

confidence: 99%

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Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond

2018

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Podocytes are a major component of the glomerular blood filtration barrier, and alterations to the morphology of their unique actin-based foot processes (FP) are a common feature of kidney disease. Adjacent FP are connected by a specialized intercellular junction known as the slit diaphragm (SD), which serves as the ultimate barrier to regulate passage of macromolecules from the blood. While the link between SD dysfunction and reduced filtration selectivity has been recognized for nearly 50 years, our understanding of the underlying molecular circuitry began only 20 years ago, sparked by the identification of NPHS1, encoding the transmembrane protein nephrin. Nephrin not only functions as the core component of the extracellular SD filtration network but also as a signaling scaffold via interactions at its short intracellular region. Phospho-regulation of several conserved tyrosine residues in this region influences signal transduction pathways which control podocyte cell adhesion, shape, and survival, and emerging studies highlight roles for nephrin phospho-dynamics in mechanotransduction and endocytosis. The following review aims to summarize the last 5 years of advancement in our knowledge of how signaling centered at nephrin directs SD barrier formation and function. We further provide insight on promising frontiers in podocyte biology, which have implications for SD signaling in the healthy and diseased kidney.

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Nephrin Suppresses Hippo Signaling through the Adaptor Proteins Nck and WTIP

Cited by 18 publications

References 31 publications

Multivalent nephrin–Nck interactions define a threshold for clustering and tyrosine-dependent nephrin endocytosis

Multivalent nephrin–Nck interactions define a threshold for clustering and tyrosine-dependent nephrin endocytosis

Role of c-Abl and nephrin in podocyte cytoskeletal remodeling induced by angiotensin II

Nephrin Signaling in the Podocyte: An Updated View of Signal Regulation at the Slit Diaphragm and Beyond

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