The transmembrane protein nephrin is a key component of the kidney glomerular slit diaphragm that is required for normal morphology and permselectivity of podocytes. It has recently been reported that tyrosine phosphorylation of the cytoplasmic tail of nephrin facilitates recruitment of several signaling proteins that regulate podocyte function. We now demonstrate that the adaptor protein ShcA is expressed in podocytes and binds phosphorylated nephrin via the SH2 domain. This interaction was mapped to three conserved tyrosine residues on nephrin (Y1176, Y1193 and Y1217). Expression of the p46/52 isoforms of ShcA was shown to repress nephrin signaling, as demonstrated by the AP-1 activity assay, whereas this effect was not seen with the p66 isoform of ShcA. Interestingly, p66ShcA is only weakly detectable in normal glomeruli, though it is significantly upregulated following podocyte injury 'in vivo', parallel with an increase in the p46/52 isoforms. We have therefore identified a novel phospho-dependent interaction between ShcA and nephrin.