Rat nephrin modulates cell morphology via the adaptor protein Nck

Li, Hongping; Zhu, Jun; Aoudjit, Lamine; Latreille, Mathieu; Kawachi, Hiroshi; Larose, Louise; Takano, Tomoko

doi:10.1016/j.bbrc.2006.08.053

Cited by 41 publications

(71 citation statements)

References 24 publications

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“…Finally, we examined the effect of the mutant nephrin-Y3F protein on nephrin signaling by Western blot analysis of glomerular lysates isolated from nephrin WT/WT and nephrin Y3F/Y3F animals. Phosphorylation of these tyrosines is required for nephrin-Nck binding in vitro 8,9,14 ; thus, we validated that this interaction was disrupted in vivo using immunoprecipitation ( Figure 2E). Consistent with the role of Nck recruitment in promoting nephrin tyrosine phosphorylation, 15 we observed a significant reduction in total nephrin tyrosine phosphorylation in nephrin Y3F/Y3F animals using a pan-phosphotyrosine antibody ( Figure 2F).…”

Section: Generation Of Nephrinmentioning

confidence: 69%

“…20 Reductions in nephrin phosphorylation, Nck/p85 binding, and Akt activation have also been detected in the puromycin aminonucleoside model of reversible podocyte injury 12,14,16,18 in parallel with increased expression of the phosphatase PTP1B, which can dephosphorylate nephrin Y1217. 58 By contrast, phosphorylation of nephrin on Y1176/Y1193 is increased with protamine sulfate as noted previously.…”

Section: Discussionmentioning

confidence: 97%

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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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Section: Generation Of Nephrinmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 97%

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

New¹,

Martín²,

Scott

et al. 2016

JASN

Self Cite

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“…However, the reduction in nephrin phosphorylation is likely due to two different mechanisms. Firstly, as the SH2 domain of Nck is the sole mediator of the interaction between phosphorylated nephrin and Nck (13,14), mutation of the SH2 domain effectively creates a version of Nck that cannot interact with nephrin and remains spatially segregated from nephrin signaling at the plasma membrane. SH2* Nck therefore does not have any effect on nephrin phosphorylation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We (15,17) and others (13,14) have demonstrated that, when phosphorylated, each of these residues can recruit the Nck family of SH2/SH3 adaptor proteins. The single Nck SH2 domain binds the phosphorylated YDXV motifs, whereas the three tandem SH3 domains mediate interactions with downstream effectors of the actin cytoskeleton, thereby providing a link between nephrin and podocyte actin dynamics.…”

mentioning

confidence: 95%

“…Targets of phosphorylation by SFKs include a number of structural components of the slit diaphragm, such as nephrin (4) and the Neph1/2/3 family (6, 7) of IgG adhesion molecules, whose phosphorylated tyrosines serve to recruit downstream signaling proteins. Phosphorylated nephrin has been reported to interact with p85 (8 -10), podocin (11,12), Nck1/2 (13)(14)(15), and phospholipase C-␥ (16), whereas phosphorylated Neph1 has been shown to interact with Grb2 (6, 7) and C-terminal Src kinase (Csk) (7).…”

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confidence: 99%

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Direct Regulation of Nephrin Tyrosine Phosphorylation by Nck Adaptor Proteins

New¹,

Chahi

Jones

2013

Journal of Biological Chemistry

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Background: Nephrin tyrosine phosphorylation by Fyn is important for its function, but the mechanisms regulating this process are not well characterized. Results: Nck promotes nephrin phosphorylation through activation of Fyn. Conclusion: Nck appears to be involved in the regulation of nephrin phosphorylation. Significance: We have identified an interaction that contributes to our understanding of the regulation of nephrin phosphorylation.

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Regulation of Nephrin Phosphorylation in Diabetes and Chronic Kidney Injury

Denhez

Geraldes

2017

Advances in Experimental Medicine and Biology

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Diabetes is the leading cause of microalbuminuria and end-stage renal failure in industrial countries. Disruption of the filtration barrier, seen in almost all nephrotic diseases and diabetes, is the result of the loss or effacement of the podocyte foot process, notably damage of proteins within the slit diaphragm such as nephrin. For many years, nephrin has been viewed as a structural component of the slit diaphragm. It is now well recognized that nephrin contains several tyrosine residues in its cytoplasmic domain, which influences the development of glomerular injury. In this review, we propose an overview of nephrin signaling pathways in kidney injury.

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Rat nephrin modulates cell morphology via the adaptor protein Nck

Cited by 41 publications

References 24 publications

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

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

Direct Regulation of Nephrin Tyrosine Phosphorylation by Nck Adaptor Proteins

Regulation of Nephrin Phosphorylation in Diabetes and Chronic Kidney Injury

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