Interaction with podocin facilitates nephrin signaling

Mutations of NPHS1 or NPHS2, the genes encoding for the glomerular podocyte proteins nephrin and podocin, cause steroid-resistant proteinuria. In addi tion, mice lacking CD2-associated protein (CD2AP) develop a nephrotic syndr ome that resembles NPHS mutations suggesting that all three proteins are es sential for the integrity of glomerular podocytes. Although the precise glo merular function of either protein remains unknown, it has been suggested t hat nephrin forms zipper-like interactions to maintain the structure of pod ocyte foot processes. We demonstrate now that nephrin is a signaling molecu le, which stimulates mitogen-activated protein kinases. Nephrin-induced sig naling is greatly enhanced by podocin, which binds to the cytoplasmic tail of nephrin. Mutational analysis suggests that abnormal or inefficient signa ling through the nephrin-podocin complex contributes to the development of podocyte dysfunction and proteinuria.