Figure 2.

Nephrin tyrosine phosphorylation regulates a diverse group of signaling processes within the podocyte. Nephrin is a single pass transmembrane protein and contains a singular extracellular (ER), transmembrane (TR), and cytoplasmic (CR) region. Nephrin’s ER contains 1 Fibronectin-like III (FNIII) motif and eight Immunoglobulin (IgG)-like regions, which allow for homophilic interactions of nephrin molecules in trans. Tyrosine residues embedded in nephrin’s CR can be loosely classified into two categories, denoted as group A or B tyrosines, based largely on their flanking sequences. These consensus sequences are conserved and influence the adaptor molecules and downstream signaling effectors that can be recruited to nephrin upon their tyrosine phosphorylation. Interactions with each group contributes to cytoskeletal organization (through Cas-Crk/1/2/L, Nck-N-WASp/Pak and/or PLC-γ1) and nephrin’s phospho-regulation [through protein tyrosine phosphatases (PTPs)], denoted in purple. Alternatively, cell survival signaling appears to be largely restricted to signaling at group A residues (through p85/PI3K-AKT), denoted in blue, while nephrin trafficking is influenced by group B signaling (through ShcA), denoted in red.