{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:26:44Z","timestamp":1790245604325,"version":"4.1.0"},"reference-count":35,"publisher":"The Company of Biologists","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,15]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1242\/dev.099408","type":"journal-article","created":{"date-parts":[[2013,12,12]],"date-time":"2013-12-12T01:15:39Z","timestamp":1386810939000},"page":"367-376","source":"Crossref","is-referenced-by-count":33,"title":["Src64B phosphorylates Dumbfounded and regulates slit diaphragm dynamics: <i>Drosophila<\/i> as a model to study nephropathies"],"prefix":"10.1242","volume":"141","author":[{"given":"Antonio S.","family":"Tutor","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC-UAM, Nicol\u00e1s Cabrera 1, 28049, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Prieto-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC-UAM, Nicol\u00e1s Cabrera 1, 28049, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"Ruiz-G\u00f3mez","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, CSIC-UAM, Nicol\u00e1s Cabrera 1, 28049, Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042607475016500_R1","doi-asserted-by":"crossref","first-page":"3408","DOI":"10.1093\/ndt\/gfm403","article-title":"The nephrin-based slit diaphragm: new insight into the signalling platform identifies targets for therapy","volume":"22","author":"Aaltonen","year":"2007","journal-title":"Nephrol. Dial. Transplant."},{"key":"2021042607475016500_R2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nbt0307-285","article-title":"A curated compendium of phosphorylation motifs","volume":"25","author":"Amanchy","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"2021042607475016500_R3","doi-asserted-by":"crossref","first-page":"13901","DOI":"10.1073\/pnas.0806983105","article-title":"A fluorescent reporter of caspase activity for live imaging","volume":"105","author":"Bardet","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042607475016500_R4","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1097\/01.ASN.0000130167.30769.55","article-title":"Signaling at the slit diaphragm","volume":"15","author":"Benzing","year":"2004","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021042607475016500_R5","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1006\/jmbi.1999.3310","article-title":"Sequence and structure-based prediction of eukaryotic protein phosphorylation sites","volume":"294","author":"Blom","year":"1999","journal-title":"J. Mol. Biol."},{"key":"2021042607475016500_R6","first-page":"43","article-title":"Alterations of the glomerular epithelium in acute aminonucleoside nephrosis. Evidence for formation of occluding junctions and epithelial cell detachment","volume":"34","author":"Caulfield","year":"1976","journal-title":"Lab. Invest."},{"key":"2021042607475016500_R7","first-page":"F1237","article-title":"Drosophila provides rapid modeling of renal development, function, and disease","volume":"299","author":"Dow","year":"2010","journal-title":"Am. J. Physiol."},{"key":"2021042607475016500_R8","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1159\/000101795","article-title":"Slit diaphragm junctional complex and regulation of the cytoskeleton","volume":"106","author":"Garg","year":"2007","journal-title":"Nephron Exp. Nephrol."},{"key":"2021042607475016500_R9","doi-asserted-by":"crossref","first-page":"8698","DOI":"10.1128\/MCB.00948-07","article-title":"Neph1 cooperates with nephrin to transduce a signal that induces actin polymerization","volume":"27","author":"Garg","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"2021042607475016500_R10","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1111\/j.1440-1827.2004.01683.x","article-title":"Key molecular events in puromycin aminonucleoside nephrosis rats","volume":"54","author":"Guan","year":"2004","journal-title":"Pathol. Int."},{"key":"2021042607475016500_R11","doi-asserted-by":"crossref","first-page":"9177","DOI":"10.1074\/jbc.M707247200","article-title":"Neph1, a component of the kidney slit diaphragm, is tyrosine-phosphorylated by the Src family tyrosine kinase and modulates intracellular signaling by binding to Grb2","volume":"283","author":"Harita","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021042607475016500_R12","doi-asserted-by":"crossref","first-page":"317852","DOI":"10.1155\/2011\/317852","article-title":"Tyrosine kinase signaling in kidney glomerular podocytes","volume":"2011","author":"Hattori","year":"2011","journal-title":"J. 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J. Physiol."},{"key":"2021042607475016500_R17","first-page":"1577","article-title":"Phosphorylation and regulatory effects of the carboxy terminus of a Drosophila src homolog","volume":"7","author":"Kussick","year":"1992","journal-title":"Oncogene"},{"key":"2021042607475016500_R18","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1046\/j.1523-1755.2003.00097.x","article-title":"Clustering-induced tyrosine phosphorylation of nephrin by Src family kinases","volume":"64","author":"Lahdenper\u00e4","year":"2003","journal-title":"Kidney Int."},{"key":"2021042607475016500_R19","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1097\/01.LAB.0000017168.26718.16","article-title":"Podocyte-associated molecules in puromycin aminonucleoside nephrosis of the rat","volume":"82","author":"Luimula","year":"2002","journal-title":"Lab. 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Med."},{"key":"2021042607475016500_R23","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nrneph.2009.108","article-title":"New insights into the role of podocytes in proteinuria","volume":"5","author":"Patrakka","year":"2009","journal-title":"Nat. Rev. Nephrol."},{"key":"2021042607475016500_R24","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.bbrc.2010.04.069","article-title":"Molecular make-up of the glomerular filtration barrier","volume":"396","author":"Patrakka","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021042607475016500_R25","first-page":"F213","article-title":"Inducible rodent models of acquired podocyte diseases","volume":"296","author":"Pippin","year":"2009","journal-title":"Am. J. Physiol."},{"key":"2021042607475016500_R26","unstructured":"Prieto-S\u00e1nchez\n              S.\n            \n           (2009). Funci\u00f3n de Dumbfounded, Sticks and stones y Polychateoid en los nefrocitos en guirnalda de Drosophila melanogaster, p 85. PhD dissertation, Universidad Aut\u00f3noma de Madrid, Madrid, Spain."},{"key":"2021042607475016500_R27","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1073\/pnas.95.5.2077","article-title":"Domain requirements for the Dock adapter protein in growth-cone signaling","volume":"95","author":"Rao","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042607475016500_R28","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/ki.2008.653","article-title":"Flying podocytes","volume":"75","author":"Simons","year":"2009","journal-title":"Kidney Int."},{"key":"2021042607475016500_R29","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.cell.2006.04.002","article-title":"Nck links nephrin to actin in kidney podocytes","volume":"125","author":"Tryggvason","year":"2006","journal-title":"Cell"},{"key":"2021042607475016500_R30","doi-asserted-by":"crossref","first-page":"20716","DOI":"10.1074\/jbc.M301689200","article-title":"Fyn binds to and phosphorylates the kidney slit diaphragm component Nephrin","volume":"278","author":"Verma","year":"2003","journal-title":"J. Biol. 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Transplant."},{"key":"2021042607475016500_R34","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1681\/ASN.2012080769","article-title":"An in vivo functional analysis system for renal gene discovery in Drosophila pericardial nephrocytes","volume":"24","author":"Zhang","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021042607475016500_R35","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1242\/dev.031609","article-title":"Sns and Kirre, the Drosophila orthologs of Nephrin and Neph1, direct adhesion, fusion and formation of a slit diaphragm-like structure in insect nephrocytes","volume":"136","author":"Zhuang","year":"2009","journal-title":"Development"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/141\/2\/367\/1322649\/367.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/141\/2\/367\/1322649\/367.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T12:09:32Z","timestamp":1619438972000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/141\/2\/367\/46419\/Src64B-phosphorylates-Dumbfounded-and-regulates"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,15]]},"references-count":35,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2014,1,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.099408","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2014,1,15]]}}}