title: Src64B phosphorylates Dumbfounded and regulates slit diaphragm dynamics: Drosophila as a model to study nephropathies.
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.
authors: Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Nicolás Cabrera 1, 28049, Madrid, Spain.
authors: Antonio S
authors: AS
authors: Tutor
authors: Silvia
authors: S
authors: Prieto-Sánchez
authors: Mar
authors: M
authors: Ruiz-Gómez
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002449:Cell Aggregation; D002460:Cell Line; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D004789:Enzyme Activation; D060730:Glomerular Filtration Barrier / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; C413082:kirre protein, Drosophila; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C075699:Src64B protein, Drosophila
keywords: Dumbfounded; Slit diaphragm; Src64B