Background: Maintenance of the kidney filtration barrier requires coordinated interactions between podocytes and the underlying glomerular basement membrane (GBM). GBM ligands bind podocyte integrins, which triggers actin-based signaling events critical for adhesion. Nck1/2 adaptors have emerged as essential regulators of podocyte cytoskeletal dynamics. However, the precise signaling mechanisms mediated by Nck1/2 adaptors in podocytes remain to be fully elucidated.
Methods: We generated podocytes deficient in Nck1 and Nck2 and used transcriptomic approaches to profile expression differences. Proteomic techniques identified specific binding partners for Nck1 and Nck2 in podocytes. We used cultured podocytes and mice deficient in Nck1 and/or Nck2, along with podocyte injury models, to comprehensively verify our findings.
Results: Compound loss of Nck1/2 altered expression of genes involved in actin binding, cell adhesion, and extracellular matrix composition. Accordingly, Nck1/2-deficient podocytes showed defects in actin organization and cell adhesion , with podocyte detachment and altered GBM morphology present . We identified distinct interactomes for Nck1 and Nck2 and uncovered a mechanism by which Nck1 and Nck2 cooperate to regulate actin bundling at focal adhesions actinin-4. Furthermore, loss of Nck1 or Nck2 resulted in increased matrix deposition , with more prominent defects in Nck2-deficient mice, consistent with enhanced susceptibility to podocyte injury.
Conclusion: These findings reveal distinct, yet complementary, roles for Nck proteins in regulating podocyte adhesion, controlling GBM composition, and sustaining filtration barrier integrity.
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http://dx.doi.org/10.1681/ASN.2021101343 | DOI Listing |
Biochem J
October 2024
Centre de recherche du Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Division Oncologie, Québec, QC, Canada.
J Mammary Gland Biol Neoplasia
July 2023
Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
Front Cardiovasc Med
August 2022
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, United States.
A better understanding of endothelial dysfunction holds promise for more effective interventions for atherosclerosis prevention and treatment. Endothelial signaling by the non-catalytic region of the tyrosine kinase (NCK) family of adaptors, consisting of NCK1 and NCK2, has been implicated in cardiovascular development and postnatal angiogenesis but its role in vascular disease remains incompletely understood. Here, we report stage- and sex-dependent effects of endothelial NCK2 signaling on arterial wall inflammation and atherosclerosis development.
View Article and Find Full Text PDFJ Am Soc Nephrol
August 2022
Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada.
Background: Maintenance of the kidney filtration barrier requires coordinated interactions between podocytes and the underlying glomerular basement membrane (GBM). GBM ligands bind podocyte integrins, which triggers actin-based signaling events critical for adhesion. Nck1/2 adaptors have emerged as essential regulators of podocyte cytoskeletal dynamics.
View Article and Find Full Text PDFJ Cell Sci
September 2021
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 7783, USA.
The non-catalytic region of tyrosine kinase (Nck) family of adaptors, consisting of Nck1 and Nck2, contributes to selectivity and specificity in the flow of cellular information by recruiting components of signaling networks. Known to play key roles in cytoskeletal remodeling, Nck adaptors modulate host cell-pathogen interactions, immune cell receptor activation, cell adhesion and motility, and intercellular junctions in kidney podocytes. Genetic inactivation of both members of the Nck family results in embryonic lethality; however, viability of mice lacking either one of these adaptors suggests partial functional redundancy.
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