The slit diaphragm: a signaling platform to regulate podocyte function.
OBJECTIVE
The discovery of nephrin and other slit diaphragm proteins dramatically expanded our knowledge of the molecular make-up of the glomerular filter of the kidney. This review focuses on the most recent evidence elucidating the dynamic functions of the slit diaphragm and stresses the importance of slit diaphragm proteins in mediating signal transduction in the podocyte.


RESULTS
Nephrin and neph molecules form specialized cell junctions in various systems in different species. The organization of these specialized cell junctions is dependent on intracellular signaling networks. There is a rapidly growing number of identified adapter and signaling molecules that are recruited to this signaling network. These proteins help to maintain programs for cell survival, cell polarity and endocytosis. The latest examples of identified signaling proteins at the slit diaphragm are fyn, p85, and calcium/calmodulin-dependent serine protein kinase. At the level of the slit insertion site, podocin seems to play a pivotal role in the establishment of a lipid-enriched signaling environment. Moreover, the protocadherin FAT1 has been identified as an organizer of actin polymerization and could therefore serve as a linker of the slit diaphragm to cytoskeletal organization.


CONCLUSIONS
From recent data, a novel concept of a highly dynamic slit protein complex is emerging. Slit diaphragm proteins are contributing to the regulation of cell polarity, cell survival and cytoskeletal organization. This concept is further supported by the fact that many clinically relevant mutations of slit diaphragm proteins interfere with signaling processes at the slit diaphragm and cause proteinuria and progressive kidney disease.
Huber
Tobias B
TB
Pathology and Immunology, Washington University St Louis, St Louis, Missouri, USA.
Benzing
Thomas
T
D004847:Epithelial Cells / Q000502:physiology*; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology*; D007678:Kidney Glomerulus / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D008565:Membrane Proteins; C113267:nephrin