Open AccessMultivalent nephrin/Nck interactions define a threshold for clustering and tyrosine-dependent nephrin endocytosis
Author(s) -
Claire Emilie Martín,
Laura A. New,
Noah J. Phippen,
Ava Keyvani Chahi,
A Mitro,
Tomoko Takano,
Tony Pawson,
Ivan M. Blasutig,
Nina Jones
Publication year - 2020
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.236877
Subject(s) - biology , nephrin , endocytosis , cluster analysis , tyrosine , microbiology and biotechnology , nexus (standard) , genetics , biochemistry , receptor , artificial intelligence , computer science , embedded system , podocyte , proteinuria , kidney
Assembly of signaling molecules into micrometer-sized clusters is driven by multivalent protein-protein interactions, such as those found within the nephrin/Nck complex. Phosphorylation on multiple tyrosines 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.