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 addition, mice lacking CD2-associated protein (CD2AP) develop a nephrotic syndrome that resembles NPHS mutations suggesting that all three proteins are essential for the integrity of glomerular podocytes. Although the precise glomerular function of either protein remains unknown, it has been suggested that nephrin forms zipper-like interactions to maintain the structure of podocyte foot processes. We demonstrate now that nephrin is a signaling molecule, which stimulates mitogen-activated protein kinases. Nephrin-induced signaling is greatly enhanced by podocin, which binds to the cytoplasmic tail of nephrin. Mutational analysis suggests that abnormal or inefficient signaling through the nephrin-podocin complex contributes to the development of podocyte dysfunction and proteinuria.
Huber
T B
TB
Renal Division, University Hospital Freiburg, Freiburg 79106, Germany.
Kottgen
M
M
Schilling
B
B
Walz
G
G
Benzing
T
T
D001483:Base Sequence; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008969:Molecular Sequence Data; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D011506:Proteins; D018808:Transcription Factor AP-1; C113267:nephrin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases