Nephrin is a single-pass type I transmembrane protein of the immunoglobulin superfamily (eight Ig-like C2 domains and a fibronectin type III repeat), expressed almost exclusively in kidney glomerular podocytes, with minor expression in brain and pancreas. It is the principal structural component of the slit diaphragm, the specialised cell-cell junction that bridges interdigitating podocyte foot processes and forms the final layer of the glomerular filtration barrier. Nephrin ectodomains from adjacent foot processes interact homophilically in trans and associate with Neph-family (KIRREL) adhesion receptors, building the zipper-like slit diaphragm. Its cytoplasmic tail acts as a phosphotyrosine signalling scaffold: Src-family kinase (FYN) phosphorylation of YDxV motifs recruits Nck SH2/SH3 adaptors that drive local actin polymerisation, and other sites recruit PI3K; podocin and CD2AP associate with the tail. Loss-of-function mutations cause congenital nephrotic syndrome of the Finnish type, with absent slit diaphragms and massive proteinuria. Mouse and zebrafish studies suggest an additional role in myoblast fusion, paralleling its Drosophila subfamily relative Sns.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:16525419 Nck adaptor proteins link nephrin to the actin cytoskeleton ... | MODIFY | Summary: IPI with NCK1 (P16333). Phosphorylated nephrin cytoplasmic YDxV motifs bind the SH2 domain of Nck adaptors, linking the slit diaphragm to actin. Reason: Generic protein binding is uninformative. The cited study maps the interaction to phosphorylated YDxV motifs of the nephrin tail that are binding motifs for the Nck SH2 domain, which supports the more informative SH2 domain binding term (nephrin is the SH2 ligand). Proposed replacements: SH2 domain binding Supporting Evidence: PMID:16525419 multiple YDxV sites that form preferred binding motifs for the Nck SH2 domain Reactome:R-HSA-373724 NCK via its SH2 domain interacts with the three phosphotyrosines (1176, 1193 and 1217) on nephrin |
| GO:0005515 protein binding | IPI PMID:21858180 Functional and spatial analysis of C. elegans SYG-1 and SYG-... | MODIFY | Summary: IPI with C. elegans SYG-1 (B1Q236), the worm Neph1/KIRREL ortholog, co-immunoprecipitated with human nephrin from HEK293T cells. Reason: Generic protein binding is uninformative. SYG-1 is a Neph-family IgSF adhesion receptor (different PANTHER subfamily from nephrin) and nephrin binds it as the heterophilic adhesion partner, as SYG-2 does; cell adhesion molecule binding (already carried by IBA) captures the function. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:21858180 both SYG-2 and nephrin could also be shown to strongly bind to SYG-1 by co-immunoprecipitation |
| GO:0005515 protein binding | IPI PMID:22662192 IQGAP1 interacts with components of the slit diaphragm compl... | REMOVE | Summary: IPI with IQGAP1 (P46940) in podocytes; IQGAP1 associates with the C-terminal half of the nephrin intracellular domain. Reason: Generic protein binding is uninformative per the protein-binding policy. The nephrin-IQGAP1 association is not disputed, but no specific molecular function of nephrin (as opposed to the IQGAP1 scaffold) is established by it. Supporting Evidence: PMID:22662192 IQGAP1, a scaffold protein involved in actin remodelling has been identified as being associated with nephrin in podocyte foot processes |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PAINT node PTN002267852 (nephrin/Sns/SYG-2 subfamily); O60500 is itself a donor. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. The IBA is consistent with membership of PTHR11640:SF136 and with human experimental localisation. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes file:human/NPHS1/NPHS1-uniprot.txt Single-pass type I |
| GO:0005886 plasma membrane | IDA PMID:17464107 Development of glomerular endothelial cells, podocytes and m... | ACCEPT | Summary: IDA from a human fetal kidney immunostaining study using nephrin as a podocyte marker. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS PMID:9660941 Positionally cloned gene for a novel glomerular protein--nep... | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-373714 | ACCEPT | Summary: TAS from the positional cloning paper describing nephrin as a putative transmembrane IgSF protein. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-373724 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-373732 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-373734 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-373747 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-451377 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-451757 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-532603 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8981534 | ACCEPT | Summary: Plasma membrane localisation of nephrin. Reason: Nephrin is a single-pass type I transmembrane IgSF protein of the podocyte plasma membrane, concentrated at the slit diaphragm between foot processes and also present on the apical membrane. Plasma membrane is correct; the slit diaphragm row records the specialised junctional location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes PMID:9660941 is a 1241-residue putative transmembrane protein of the immunoglobulin |
| GO:0005911 cell-cell junction | IBA GO_REF:0000033 | MODIFY | Summary: IBA cell-cell junction from PTN002267852. Reason: Correct but general. The specific cell-cell junction where human nephrin acts is the slit diaphragm (is_a cell-cell junction), shown by immunogold EM in human glomeruli and already carried by this gene (ISS row). The family-level node term is appropriate for Sns/SYG-2 but for vertebrate nephrin the slit diaphragm is the supported refinement. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN002267852 SUPPORTS TRANSFER Node spans the nephrin/Sns/SYG-2 subfamily; cell-cell junction is the right family-level term. The MODIFY only sharpens it to slit diaphragm for vertebrate nephrin and does not dispute the transfer. Proposed replacements: slit diaphragm Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes |
| GO:0005925 focal adhesion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA focal adhesion transferred from mouse Nphs1 via Ensembl Compara. Reason: Nephrin is a slit diaphragm (cell-cell junction) protein; there is no human evidence placing it in cell-matrix focal adhesions, and the podocyte foot process sole contacts the GBM through integrins rather than nephrin. Likely reflects cultured-cell observations in mouse; not a characteristic location. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes |
| GO:0007519 skeletal muscle tissue development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA skeletal muscle tissue development from mouse ortholog. Reason: The mouse/zebrafish evidence is that loss of nephrin gives poorly developed muscle (zebrafish morphants) and incompletely fused myotubes (mouse KO myoblasts). Muscle tissue development is a downstream organismal phenotype; the cellular-level contribution, if any, is myoblast fusion (kept non-core separately). No human evidence. Supporting Evidence: PMID:19470472 in poorly developed muscles and incompletely fused myotubes, respectively. |
| GO:0007520 myoblast fusion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA myoblast fusion from mouse Nphs1 (Sohn et al. 2009). Reason: Nephrin is in the same PANTHER subfamily (SF136) as fly Sns, whose myoblast adhesion/fusion role is well established, and mouse nephrin-KO myoblasts fuse poorly in vitro. However, PAINT did not propagate myoblast fusion from node PTN002267852 despite fly donors carrying it, the vertebrate evidence is necessity-level, and there is no human data. Kept as a plausible non-core role; not core. Supporting Evidence: PMID:19470472 suggest that nephrin plays a role in secondary fusion of myoblasts into nascent |
| GO:0017022 myosin binding | IPI PMID:21402783 Motor protein Myo1c is a podocyte protein that facilitates t... | KEEP AS NON CORE | Summary: IPI with MYO1C (O00159); Myo1c binds nephrin and influences its membrane localisation in podocytes. Reason: The interaction is reported (abstract: Myo1c also binds nephrin); myosin binding is a reasonable but peripheral descriptor reflecting nephrin trafficking by a motor rather than a core activity of nephrin. Supporting Evidence: PMID:21402783 Myo1c also binds nephrin |
| GO:0032836 glomerular basement membrane development | IEP PMID:17464107 Development of glomerular endothelial cells, podocytes and m... | MARK AS OVER ANNOTATED | Summary: IEP glomerular basement membrane development from immunostaining of human fetal kidneys, where nephrin served as a podocyte marker. Reason: The study used nephrin only as a podocyte marker during glomerular staging; expression timing is not evidence that nephrin participates in GBM development. Nephrin is a slit diaphragm protein, not a GBM constituent, and the nephrin KO phenotype is loss of the slit diaphragm and foot processes. Supporting Evidence: PMID:17464107 nephrin, a marker PMID:11136707 effacement of podocyte foot processes and absence of the slit diaphragm, |
| GO:0035418 protein localization to synapse | IGI PMID:21858180 Functional and spatial analysis of C. elegans SYG-1 and SYG-... | KEEP AS NON CORE | Summary: IGI: human nephrin expressed in C. elegans vulval epithelial cells rescues syg-2 mutant synapse mislocalisation, restoring SYG-1 localisation to the primary synaptic region. Reason: A heterologous complementation result showing that human nephrin can substitute for the worm SYG-2 trans-adhesion partner that captures SYG-1 at synaptic sites. It demonstrates functional conservation of the adhesion module, but a synaptic role for nephrin in humans has not been established; non-core. Supporting Evidence: PMID:21858180 Expression of human nephrin can rescue defective synaptogenesis in syg-2 mutants |
| GO:0036057 slit diaphragm | ISS GO_REF:0000024 | ACCEPT | Summary: ISS slit diaphragm from rat nephrin; human nephrin directly localised to the slit diaphragm by immunogold EM. Reason: Core location. Human experimental data place nephrin at the slit diaphragm between podocyte foot processes; Reactome and UniProt describe it as the key structural component of the SD. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes Reactome:R-HSA-373732 Nephrin (NPHS1) is the critical structural component within the slit diaphragm. |
| GO:0036060 slit diaphragm assembly | IEA GO_REF:0000107 | ACCEPT | Summary: Slit diaphragm assembly. Reason: Core process. Nephrin is the principal structural component of the slit diaphragm: NPHS1 patients and Nphs1-null mice lack the slit diaphragm, and nephrin molecules from adjacent foot processes interact in trans to build the zipper-like SD. Nephrin contributes the structural adhesive unit of the junction, so it participates in (not merely is required for) its assembly. In flies the SF136 member Sns is likewise needed for nephrocyte diaphragm formation. Supporting Evidence: PMID:11136707 effacement of podocyte foot processes and absence of the slit diaphragm, PMID:10393930 characterized by massive proteinuria already in utero and lack of slit diaphragm Reactome:R-HSA-373732 Nephrin molecules of adjacent foot processes from neighboring podocytes interact |
| GO:0036060 slit diaphragm assembly | ISS GO_REF:0000024 | ACCEPT | Summary: Slit diaphragm assembly. Reason: Core process. Nephrin is the principal structural component of the slit diaphragm: NPHS1 patients and Nphs1-null mice lack the slit diaphragm, and nephrin molecules from adjacent foot processes interact in trans to build the zipper-like SD. Nephrin contributes the structural adhesive unit of the junction, so it participates in (not merely is required for) its assembly. In flies the SF136 member Sns is likewise needed for nephrocyte diaphragm formation. Supporting Evidence: PMID:11136707 effacement of podocyte foot processes and absence of the slit diaphragm, PMID:10393930 characterized by massive proteinuria already in utero and lack of slit diaphragm Reactome:R-HSA-373732 Nephrin molecules of adjacent foot processes from neighboring podocytes interact |
| GO:0036060 slit diaphragm assembly | TAS PMID:9660941 Positionally cloned gene for a novel glomerular protein--nep... | ACCEPT | Summary: TAS from the positional cloning paper (crucial role in the kidney filtration barrier). Reason: Core process. Nephrin is the principal structural component of the slit diaphragm: NPHS1 patients and Nphs1-null mice lack the slit diaphragm, and nephrin molecules from adjacent foot processes interact in trans to build the zipper-like SD. Nephrin contributes the structural adhesive unit of the junction, so it participates in (not merely is required for) its assembly. In flies the SF136 member Sns is likewise needed for nephrocyte diaphragm formation. Supporting Evidence: PMID:11136707 effacement of podocyte foot processes and absence of the slit diaphragm, PMID:10393930 characterized by massive proteinuria already in utero and lack of slit diaphragm Reactome:R-HSA-373732 Nephrin molecules of adjacent foot processes from neighboring podocytes interact |
| GO:0050839 cell adhesion molecule binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cell adhesion molecule binding from PTN002267852. Reason: Core function. Human nephrin ectodomains bind each other homophilically and nephrin binds Neph-family IgSF adhesion receptors (KIRREL proteins; worm SYG-1) heterophilically, as fly Sns binds Kirre. Consistent with the PAINT node placement. Supporting Evidence: PMID:14633607 homophilic interactions that could promote cellular contacts through direct PMID:21858180 both SYG-2 and nephrin could also be shown to strongly bind to SYG-1 by co-immunoprecipitation Reactome:R-HSA-373714 Nephrin (NPHS1) forms heterodimers with KIRREL (NEPH1) molecules |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: HDA: detected in urinary exosome proteomics. Reason: High-throughput detection in urinary exosomes likely reflects shedding of podocyte membrane into urine; not a site of nephrin function. Supporting Evidence: |
| GO:0071944 cell periphery | IEA GO_REF:0000107 | TOO GENERAL | Summary: IEA cell periphery from mouse ortholog. Reason: True but uninformative; plasma membrane and slit diaphragm, both accepted in this review, entail it. Supporting Evidence: PMID:10393930 at the slit between podocyte foot processes |
| GO:0072015 podocyte development | IEP PMID:17464107 Development of glomerular endothelial cells, podocytes and m... | KEEP AS NON CORE | Summary: IEP podocyte development; nephrin staining first appears at S-shaped body stage. Reason: Nephrin contributes to podocyte maturation through building the slit diaphragm and supporting foot process formation (KO shows foot process effacement and absent SD). The IEP evidence itself is marker expression timing; the specific contribution is captured by slit diaphragm assembly. Kept as non-core developmental process. Supporting Evidence: PMID:17464107 Staining of alpha-SMA and nephrin was first observed in the S stage. PMID:11136707 effacement of podocyte foot processes and absence of the slit diaphragm, |
| GO:0098609 cell-cell adhesion | IBA GO_REF:0000033 | MODIFY | Summary: IBA cell-cell adhesion from PTN002267852. Reason: Correct but general. Human nephrin mediates homophilic cell-cell adhesion (recombinant ectodomain binding and aggregation of transfected cells) and heterophilic adhesion with Neph-family partners (SYG-1/KIRREL), mirroring fly Sns-Kirre. Both specific descendants are listed. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN002267852 SUPPORTS TRANSFER Cell-cell adhesion is correctly inherited across the subfamily; the MODIFY refines it to the homophilic and heterophilic modes shown experimentally for human nephrin and does not dispute the transfer. Proposed replacements: homophilic cell-cell adhesion heterophilic cell-cell adhesion Supporting Evidence: PMID:14633607 homophilic interactions that could promote cellular contacts through direct PMID:14633607 mouse podocyte cell line overexpressing full-length human nephrin formed PMID:21858180 both SYG-2 and nephrin could also be shown to strongly bind to SYG-1 by co-immunoprecipitation |
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Download this section (compressed HTML)Q: Should nephrin's phosphotyrosine-scaffold role in Nck-dependent actin polymerisation be captured as a process annotation (e.g. regulation of actin filament polymerization), or does that belong only to Nck/N-WASP with nephrin as the recruiting receptor?
Q: Does nephrin act cell-autonomously in mammalian myoblast fusion, and why did PAINT not propagate myoblast fusion from the nephrin/Sns node despite fly donor evidence?
Experiment: Conditional muscle-specific Nphs1 deletion in mouse to test a cell-autonomous role in secondary myoblast fusion in vivo, independent of renal lethality.
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