CD2AP/CIN85 balance determines receptor tyrosine kinase signaling response in podocytes.
Defects in podocyte signaling are the basis of many inherited glomerular diseases leading to glomerulosclerosis. CD2-associated protein (CD2AP) is highly expressed in podocytes and is considered to play an important role in the maintenance of the glomerular slit diaphragm. Mice deficient for CD2AP (CD2AP(-/-)) appear normal at birth but develop a rapid onset nephrotic syndrome at 3 weeks of age. We demonstrate that impaired intracellular signaling with subsequent podocyte damage is the reason for this delayed podocyte injury in CD2AP(-/-) mice. We document that CD2AP deficiency in podocytes leads to diminished signal initiation and termination of signaling pathways mediated by receptor tyrosine kinases (RTKs). In addition, we demonstrate that CIN85, a paralog of CD2AP, is involved in termination of RTK signaling in podocytes. CIN85 protein expression is increased in CD2AP(-/-) podocytes in vitro. Stimulation of CD2AP(-/-) podocytes with various growth factors, including insulin-like growth factor 1, vascular endothelial growth factor, and fibroblast growth factor, resulted in a significantly decreased phosphatidylinositol 3-kinase/AKT and ERK signaling response. Moreover, increased CIN85 protein is detectable in podocytes in diseased CD2AP(-/-) mice, leading to decreased base-line activation of ERK and decreased phosphorylation after growth factor stimulation in vivo. Because repression of CIN85 protein leads to a restored RTK signaling response, our results support an important role of CD2AP/CIN85 protein balance in the normal signaling response of podocytes.
Tossidou
Irini
I
Division of Nephrology, Department of Medicine, and Division of Pediatric Hematology and Oncology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany.
Kardinal
Christian
C
Peters
Imke
I
Kriz
Wilhelm
W
Shaw
Andrey
A
Dikic
Ivan
I
Tkachuk
Sergej
S
Dumler
Inna
I
Haller
Hermann
H
Schiffer
Mario
M
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D009363:Neoplasm Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C498782:Sh3kbp1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases