- 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.
MetadatenAuthor: | Irini TossidouGND, Christian KardinalGND, Imke PetersGND, Wilhelm KrizORCiDGND, Andrey ShawORCiDGND, Ivan ĐikićORCiDGND, Sergej Tkachuk, Inna DumlerGND, Hermann HallerGND, Mario SchifferORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-763032 |
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DOI: | https://doi.org/10.1074/jbc.M608519200 |
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ISSN: | 0021-9258 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/17213204 |
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Parent Title (English): | Journal of biological chemistry |
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Publisher: | American Society for Biochemistry and Molecular Biology Publications |
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Place of publication: | Bethesda, Md |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2021/01/04 |
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Year of first Publication: | 2007 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2024/04/25 |
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Volume: | 282.2007 |
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Issue: | 10 |
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Page Number: | 8 |
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First Page: | 7457 |
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Last Page: | 7464 |
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Institutes: | Medizin |
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Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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| 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - CC BY - Namensnennung 4.0 International |
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