TY  - JOUR
A1  - Tossidou, Irini
A1  - Kardinal, Christian
A1  - Peters, Imke
A1  - Kriz, Wilhelm
A1  - Shaw, Andrey
A1  - Đikić, Ivan
A1  - Tkachuk, Sergej
A1  - Dumler, Inna
A1  - Haller, Hermann
A1  - Schiffer, Mario
T1  - CD2AP/CIN85 balance determines receptor tyrosine kinase signaling response in podocytes
T2  - Journal of biological chemistry
N2  - 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.
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/76303
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-763032
SN  - 0021-9258
VL  - 282.2007
IS  - 10
SP  - 7457
EP  - 7464
PB  - American Society for Biochemistry and Molecular Biology Publications
CY  - Bethesda, Md
ER  -