RRC ID 28893
Author Tutor AS, Prieto-Sánchez S, Ruiz-Gómez M.
Title Src64B phosphorylates Dumbfounded and regulates slit diaphragm dynamics: Drosophila as a model to study nephropathies.
Journal Development
Abstract Drosophila nephrocytes are functionally homologous to vertebrate kidney podocytes. Both share the presence of slit diaphragms that function as molecular filters during the process of blood and haemolymph ultrafiltration. The protein components of the slit diaphragm are likewise conserved between flies and humans, but the mechanisms that regulate slit diaphragm dynamics in response to injury or nutritional changes are still poorly characterised. Here, we show that Dumbfounded/Neph1, a key diaphragm constituent, is a target of the Src kinase Src64B. Loss of Src64B activity leads to a reduction in the number of diaphragms, and this effect is in part mediated by loss of Dumbfounded/Neph1 tyrosine phosphorylation. The phosphorylation of Duf by Src64B, in turn, regulates Duf association with the actin regulator Dock. We also find that diaphragm damage induced by administration of the drug puromycin aminonucleoside (PAN model) directly associates with Src64B hyperactivation, suggesting that diaphragm stability is controlled by Src-dependent phosphorylation of diaphragm components. Our findings indicate that the balance between diaphragm damage and repair is controlled by Src-dependent phosphorylation of diaphragm components, and point to Src family kinases as novel targets for the development of pharmacological therapies for the treatment of kidney diseases that affect the function of the glomerular filtration barrier.
Volume 141(2)
Pages 367-76
Published 2014-1
DOI 10.1242/dev.099408
PII dev.099408
PMID 24335255
MeSH Animals Animals, Genetically Modified Cell Aggregation Cell Line Disease Models, Animal Drosophila Proteins / chemistry Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster / genetics Drosophila melanogaster / growth & development Drosophila melanogaster / metabolism* Enzyme Activation Glomerular Filtration Barrier / cytology Glomerular Filtration Barrier / metabolism* Humans Kidney Diseases / etiology Kidney Diseases / metabolism* Kidney Diseases / pathology Membrane Proteins / chemistry Membrane Proteins / genetics Membrane Proteins / metabolism* Microscopy, Electron, Transmission Muscle Proteins / chemistry Muscle Proteins / genetics Muscle Proteins / metabolism* Phosphorylation Protein-Tyrosine Kinases / genetics Protein-Tyrosine Kinases / metabolism* Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism* Tyrosine / chemistry
IF 5.763
Times Cited 17