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• W2803593737 abstract "•Deep proteome and transcriptome analyses of native podocytes unravel druggable targets•Static and dynamic proteomics uncover features of podocyte identity and proteostasis•Candidate genes for nephrotic syndrome were predicted based on multi-omic integration•FARP1 is a previously unreported candidate gene for human proteinuric kidney disease Damage to and loss of glomerular podocytes has been identified as the culprit lesion in progressive kidney diseases. Here, we combine mass spectrometry-based proteomics with mRNA sequencing, bioinformatics, and hypothesis-driven studies to provide a comprehensive and quantitative map of mammalian podocytes that identifies unanticipated signaling pathways. Comparison of the in vivo datasets with proteomics data from podocyte cell cultures showed a limited value of available cell culture models. Moreover, in vivo stable isotope labeling by amino acids uncovered surprisingly rapid synthesis of mitochondrial proteins under steady-state conditions that was perturbed under autophagy-deficient, disease-susceptible conditions. Integration of acquired omics dimensions suggested FARP1 as a candidate essential for podocyte function, which could be substantiated by genetic analysis in humans and knockdown experiments in zebrafish. This work exemplifies how the integration of multi-omics datasets can identify a framework of cell-type-specific features relevant for organ health and disease. Damage to and loss of glomerular podocytes has been identified as the culprit lesion in progressive kidney diseases. Here, we combine mass spectrometry-based proteomics with mRNA sequencing, bioinformatics, and hypothesis-driven studies to provide a comprehensive and quantitative map of mammalian podocytes that identifies unanticipated signaling pathways. Comparison of the in vivo datasets with proteomics data from podocyte cell cultures showed a limited value of available cell culture models. Moreover, in vivo stable isotope labeling by amino acids uncovered surprisingly rapid synthesis of mitochondrial proteins under steady-state conditions that was perturbed under autophagy-deficient, disease-susceptible conditions. Integration of acquired omics dimensions suggested FARP1 as a candidate essential for podocyte function, which could be substantiated by genetic analysis in humans and knockdown experiments in zebrafish. This work exemplifies how the integration of multi-omics datasets can identify a framework of cell-type-specific features relevant for organ health and disease. Diseases involving glomeruli, the filtration units of the kidney, are a leading cause of chronic kidney disease (CKD), which affects approximately 15% of all Americans (Meguid El Nahas and Bello, 2005Meguid El Nahas A. Bello A.K. Chronic kidney disease: the global challenge.Lancet. 2005; 365: 331-340Abstract Full Text Full Text PDF PubMed Scopus (820) Google Scholar, CDCCDC. Chronic Kidney Disease (CKD) Surveillance Project. https://nccd.cdc.gov/ckd.Google Scholar) and substantially increases cardiovascular events. Despite recent advances in the understanding of glomerular biology, treatment of these disorders has remained extraordinarily challenging in many cases. The podocyte is a postmitotic, neuron-like shaped epithelial cell with limited capacity for self-renewal. Podocytes are essential to maintain a physiological blood-urine barrier (Pavenstädt et al., 2003Pavenstädt H. Kriz W. Kretzler M. Cell biology of the glomerular podocyte.Physiol. Rev. 2003; 83: 253-307Crossref PubMed Scopus (1111) Google Scholar), and deterioration of podocyte function and subsequent proteinuria are critical accelerators of renal functional decline in disease states. Because of considerable metabolic and mechanical stress, the podocyte needs to maintain its proteome—a prerequisite to maintain its architecture, cytoskeletal integrity, signal transduction, and metabolic function. Interference with any of these functions—for instance, as an inherited gene defect in humans (Boute et al., 2000Boute N. Gribouval O. Roselli S. Benessy F. Lee H. Fuchshuber A. Dahan K. Gubler M.C. Niaudet P. Antignac C. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.Nat. Genet. 2000; 24: 349-354Crossref PubMed Scopus (1128) Google Scholar, Kaplan et al., 2000Kaplan J.M. Kim S.H. North K.N. Rennke H. Correia L.A. Tong H.Q. Mathis B.J. Rodríguez-Pérez J.C. Allen P.G. Beggs A.H. Pollak M.R. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis.Nat. Genet. 2000; 24: 251-256Crossref PubMed Scopus (985) Google Scholar, Kestilä et al., 1998Kestilä M. Lenkkeri U. Männikkö M. Lamerdin J. McCready P. Putaala H. Ruotsalainen V. Morita T. Nissinen M. Herva R. et al.Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome.Mol. Cell. 1998; 1: 575-582Abstract Full Text Full Text PDF PubMed Scopus (1472) Google Scholar, Reiser et al., 2005Reiser J. Polu K.R. Möller C.C. Kenlan P. Altintas M.M. Wei C. Faul C. Herbert S. Villegas I. Avila-Casado C. et al.TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function.Nat. Genet. 2005; 37: 739-744Crossref PubMed Scopus (614) Google Scholar)—leads to proteinuria, podocyte loss, glomerular scarring and, ultimately, chronic kidney disease. Despite recent progress in the understanding of genetics and signaling of proteinuric kidney disease, the molecular identity of the podocyte is not defined, and it is unclear how its function could be targeted therapeutically. Abundant information regarding podocyte mRNA expression patterns has been gathered recently (Brunskill et al., 2011Brunskill E.W. Georgas K. Rumballe B. Little M.H. Potter S.S. Defining the molecular character of the developing and adult kidney podocyte.PLoS ONE. 2011; 6: e24640Crossref PubMed Scopus (94) Google Scholar, Fu et al., 2016Fu J. Wei C. Lee K. Zhang W. He W. Chuang P. Liu Z. He J.C. Comparison of Glomerular and Podocyte mRNA Profiles in Streptozotocin-Induced Diabetes.J. Am. Soc. Nephrol. 2016; 27: 1006-1014Crossref PubMed Scopus (27) Google Scholar, Kann et al., 2015Kann M. Ettou S. Jung Y.L. Lenz M.O. Taglienti M.E. Park P.J. Schermer B. Benzing T. Kreidberg J.A. Genome-Wide Analysis of Wilms’ Tumor 1-Controlled Gene Expression in Podocytes Reveals Key Regulatory Mechanisms.J. Am. Soc. Nephrol. 2015; 26: 2097-2104Crossref PubMed Scopus (63) Google Scholar), and integrative genomic studies have enormous potential in classifying human podocyte disease and pathophysiology (Hodgin et al., 2013Hodgin J.B. Nair V. Zhang H. Randolph A. Harris R.C. Nelson R.G. Weil E.J. Cavalcoli J.D. Patel J.M. Brosius 3rd, F.C. Kretzler M. Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.Diabetes. 2013; 62: 299-308Crossref PubMed Scopus (112) Google Scholar, Ju et al., 2012Ju W. Smith S. Kretzler M. Genomic biomarkers for chronic kidney disease.Transl. Res. 2012; 159: 290-302Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, Sampson et al., 2015Sampson M.G. Hodgin J.B. Kretzler M. Defining nephrotic syndrome from an integrative genomics perspective.Pediatr. Nephrol. Berl. Ger. 2015; 30 (quiz 59): 51-63Crossref PubMed Scopus (13) Google Scholar, Susztak, 2014Susztak K. Understanding the epigenetic syntax for the genetic alphabet in the kidney.J. Am. Soc. Nephrol. 2014; 25: 10-17Crossref PubMed Scopus (47) Google Scholar). However, several studies from different fields found that absolute abundances of mRNA and protein abundances correlate only moderately. Indeed, transcript levels can only explain one- to two-thirds of protein levels, underlining the importance of post-transcriptional control (Liu et al., 2016Liu Y. Beyer A. Aebersold R. On the Dependency of Cellular Protein Levels on mRNA Abundance.Cell. 2016; 165: 535-550Abstract Full Text Full Text PDF PubMed Scopus (913) Google Scholar, Vogel and Marcotte, 2012Vogel C. Marcotte E.M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses.Nat. Rev. Genet. 2012; 13: 227-232Crossref PubMed Scopus (2066) Google Scholar). In recent years, it became feasible to investigate the entity of proteins, the proteome, at an unprecedented depth (Mann et al., 2013Mann M. Kulak N.A. Nagaraj N. Cox J. The coming age of complete, accurate, and ubiquitous proteomes.Mol. Cell. 2013; 49: 583-590Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). As a result, proteins can be resolved and quantified relatively and absolutely, culminating in a near-comprehensive mass spectrometry-based expression map of the human proteome (Kim et al., 2014Kim M.-S. Pinto S.M. Getnet D. Nirujogi R.S. Manda S.S. Chaerkady R. Madugundu A.K. Kelkar D.S. Isserlin R. Jain S. et al.A draft map of the human proteome.Nature. 2014; 509: 575-581Crossref PubMed Scopus (1298) Google Scholar, Wilhelm et al., 2014Wilhelm M. Schlegl J. Hahne H. Gholami A.M. Lieberenz M. Savitski M.M. Ziegler E. Butzmann L. Gessulat S. Marx H. et al.Mass-spectrometry-based draft of the human proteome.Nature. 2014; 509: 582-587Crossref PubMed Scopus (1159) Google Scholar). In addition, in vivo stable amino acid isotope labeling strategies opened new avenues for the quantification of protein dynamics when used in pulse experiments (Krüger et al., 2008Krüger M. Moser M. Ussar S. Thievessen I. Luber C.A. Forner F. Schmidt S. Zanivan S. Fässler R. Mann M. SILAC mouse for quantitative proteomics uncovers kindlin-3 as an essential factor for red blood cell function.Cell. 2008; 134: 353-364Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, Savas et al., 2012Savas J.N. Toyama B.H. Xu T. Yates 3rd, J.R. Hetzer M.W. Extremely long-lived nuclear pore proteins in the rat brain.Science. 2012; 335: 942Crossref PubMed Scopus (172) Google Scholar, Toyama et al., 2013Toyama B.H. Savas J.N. Park S.K. Harris M.S. Ingolia N.T. Yates 3rd, J.R. Hetzer M.W. Identification of long-lived proteins reveals exceptional stability of essential cellular structures.Cell. 2013; 154: 971-982Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar). The aim of this study was to generate a quantitative and integrative map of the podocyte proteome, both static and dynamic, and its transcriptome to gain novel and unbiased insights into podocyte biology. To demonstrate the applications of this “atlas,” we conducted orthogonal hypothesis-driven studies that supported the presence of unanticipated molecular mechanisms maintaining podocyte protein homeostasis and function. GFP-positive mouse podocytes and tomato-positive non-podocyte glomerular cells were isolated from native glomeruli of an hNPHS2Cre∗mT/mG mouse using fluorescence-activated cell sorting (FACS) (Boerries et al., 2013Boerries M. Grahammer F. Eiselein S. Buck M. Meyer C. Goedel M. Bechtel W. Zschiedrich S. Pfeifer D. Laloë D. et al.Molecular fingerprinting of the podocyte reveals novel gene and protein regulatory networks.Kidney Int. 2013; 83: 1052-1064Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Podocytes expressed GFP, whereas all other viable glomerular non-podocyte cells expressed tomato red fluorescent protein (Figure 1A). A work flow for “deep mapping” of transcriptome, proteome, and proteome dynamics was applied to both podocytes and non-podocytes (Kulak et al., 2014Kulak N.A. Pichler G. Paron I. Nagaraj N. Mann M. Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells.Nat. Methods. 2014; 11: 319-324Crossref PubMed Scopus (777) Google Scholar). Quality control of the dataset demonstrated a clear separation between both samples (Figure S1). This approach identified, in total, more than 9,000 different proteins (Tables S1 and S2). We performed absolute quantification of 6,979 proteins using the intensity-based absolute quantification (iBAQ) approach (Table S2). This proteomics parameter is relative to copy numbers in a given sample (Kohli et al., 2014Kohli P. Bartram M.P. Habbig S. Pahmeyer C. Lamkemeyer T. Benzing T. Schermer B. Rinschen M.M. Label-free quantitative proteomic analysis of the YAP/TAZ interactome.Am. J. Physiol. Cell Physiol. 2014; 306: C805-C818Crossref PubMed Scopus (46) Google Scholar, Schwanhäusser et al., 2011Schwanhäusser B. Busse D. Li N. Dittmar G. Schuchhardt J. Wolf J. Chen W. Selbach M. Global quantification of mammalian gene expression control.Nature. 2011; 473: 337-342Crossref PubMed Scopus (3473) Google Scholar). Cytoskeletal proteins were highly represented in the dataset (Figure 1A). The dynamic range of the podocyte proteome copy numbers comprises seven orders of magnitude (Figure 1B). We mapped genes associated with focal segmental glomerular sclerosis or hereditary nephrotic syndrome on this dataset (Figure 1C; top 10 genes in Figure 1D; Bierzynska et al., 2015Bierzynska A. Soderquest K. Koziell A. Genes and podocytes - new insights into mechanisms of podocytopathy.Front. Endocrinol. (Lausanne). 2015; 5: 226Crossref PubMed Scopus (46) Google Scholar). These “disease-associated genes,” although only comprising 35 of 7,000 (0.5%) absolutely quantified proteins, contributed approximately 4% of the podocyte protein mass, with cytoskeletal proteins like Actn4 and Arhgdia contributing most to this amount (Figure 1D). Several other known podocyte genes (e.g., Trpc6) were identified but could not be quantified because of their low abundance. To estimate the absolute protein quantity based on the data and determine protein concentrations or copy numbers per cell, we applied a recently developed algorithm on our dataset (“proteomic ruler”) (Wiśniewski et al., 2014Wiśniewski J.R. Hein M.Y. Cox J. Mann M. A “proteomic ruler” for protein copy number and concentration estimation without spike-in standards.Mol. Cell. Proteomics. 2014; 13: 3497-3506Crossref PubMed Scopus (261) Google Scholar). This provides a starting point to determine the stoichiometries of known protein complexes; for example, the prominent transmembrane slit diaphragm complex within native mouse podocytes, which comprises podocin-Neph1-Nephrin-Fat1 with a copy number ratio of ∼10:2:1:0.5 (Figure 1E), indicating that podocin is by far the most abundant slit diaphragm protein within podocytes (Grahammer et al., 2013Grahammer F. Schell C. Huber T.B. The podocyte slit diaphragm--from a thin grey line to a complex signalling hub.Nat. Rev. Nephrol. 2013; 9: 587-598Crossref PubMed Scopus (134) Google Scholar). Protein abundance is determined by the rate of transcription but also a result of protein stability and posttranslational processing. To identify the determinants of podocyte protein copy number abundance, we performed comparison with a transcriptomic copy number analysis performed by mRNA sequencing. Our dataset was similar to previously published mRNA sequencing (mRNA-seq) analyses but demonstrated a greater depth upon analysis with the same parameters (Figure 2A; Table S3; Figure S2). Enrichment analyses demonstrated overrepresentation of several known pathways enriched on mRNA levels, among these extracellular matrix (ECM) synthesis and nephrin interactions (Figure 2B; Figures S2E–S2I; Brunskill et al., 2011Brunskill E.W. Georgas K. Rumballe B. Little M.H. Potter S.S. Defining the molecular character of the developing and adult kidney podocyte.PLoS ONE. 2011; 6: e24640Crossref PubMed Scopus (94) Google Scholar). To unravel the correlation of transcriptomic data with proteomic data as a whole, iBAQ data were correlated with the transcriptomic (tpm) values, but the correlation was rather weak (Figure 2C). The correlation was stronger for podocytes compared with non-podocytes (Figure 2D). We checked which proteins were specifically stabilized or destabilized posttranscriptionally using 2D enrichment (Cox and Mann, 2012Cox J. Mann M. 1D and 2D annotation enrichment: a statistical method integrating quantitative proteomics with complementary high-throughput data.BMC Bioinformatics. 2012; 13: S12Crossref PubMed Scopus (339) Google Scholar). This algorithm can be used to visualize statistically significant distributions of protein annotations in a 2D space between different “omics” datasets (Cox and Mann, 2012Cox J. Mann M. 1D and 2D annotation enrichment: a statistical method integrating quantitative proteomics with complementary high-throughput data.BMC Bioinformatics. 2012; 13: S12Crossref PubMed Scopus (339) Google Scholar). The analysis revealed that ECM protein expression was decreased as expected by the respective mRNA expression, which would be expected because of loss of podocyte-produced ECM proteins excreted as part of the glomerular basement membrane assembly (Figure 2E, blue). Proteins involved in controlling metabolism were largely stabilized (Figure 2E, magenta, green). These proteins included glycolysis gene products and proteins involved in amino acid biosynthesis. Most of the genes mutated in genetic forms of proteinuria or nephrotic syndrome encode for podocyte-enriched genes. Therefore, we next analyzed whether we could expand the list of known podocyte-enriched proteins compared with other glomerular cells. Using stringent statistical cutoff values for quantification, we found 551 podocyte-enriched proteins (Figure 3A; Table S2); among these were many gene products currently known to be associated with hereditary nephrotic syndrome (Sadowski et al., 2015Sadowski C.E. Lovric S. Ashraf S. Pabst W.L. Gee H.Y. Kohl S. Engelmann S. Vega-Warner V. Fang H. Halbritter J. et al.SRNS Study GroupA single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.J. Am. Soc. Nephrol. 2015; 26: 1279-1289Crossref PubMed Scopus (304) Google Scholar). Figures S3 and S4A depict standardized stainings of 190 proteins that have a “medium” or “high” staining intensity in the human protein atlas (Uhlén et al., 2015Uhlén M. Fagerberg L. Hallström B.M. Lindskog C. Oksvold P. Mardinoglu A. Sivertsson Å. Kampf C. Sjöstedt E. Asplund A. et al.Proteomics. Tissue-based map of the human proteome.Science. 2015; 347: 1260419Crossref PubMed Scopus (4822) Google Scholar). A systematic Medline search of these 190 proteins revealed that the majority were not explicitly linked to podocytes (Table S4). We performed statistical enrichment for overrepresentation of protein domains in all 551 proteins enriched in podocytes (Figure 3B). Significantly enriched protein domains were Fn3 and immunoglobulin G (IgG)-like domains (e.g., in Nephrin), PDZ domains (e.g., in ezrin and Par-3), i-set domains (e.g., in nephrin and VCAM/NCAM), CH domain (e.g., in actinin-4), and FERM domain proteins (e.g., in ezrin) or tetraspanins (e.g., CD151). On a global level, podocyte-specific proteins were significantly reduced for mitochondria as well as RNA and DNA binding proteins (Figure 3C) and enriched for signaling receptors, cytoskeleton-associated proteins, GTPase-associated proteins, membrane proteins, and (phospho)lipid-modifying proteins (Figure 3D). To demonstrate that this resource may be used to find essential podocyte proteins, we analyzed the effect of knockdown of one candidate podocyte-enriched gene in Drosophila nephrocytes, an established model of podocyte function (Weavers et al., 2009Weavers H. Prieto-Sánchez S. Grawe F. Garcia-López A. Artero R. Wilsch-Bräuninger M. Ruiz-Gómez M. Skaer H. Denholm B. The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm.Nature. 2009; 457: 322-326Crossref PubMed Scopus (186) Google Scholar, Zhang et al., 2013Zhang F. Zhao Y. Han Z. An in vivo functional analysis system for renal gene discovery in Drosophila pericardial nephrocytes.J. Am. Soc. Nephrol. 2013; 24: 191-197Crossref PubMed Scopus (59) Google Scholar). We knocked down Tsp26A, the Drosophila homolog of TSP5 and TSP15, two newly identified podocyte-enriched proteins that are representatives of the protein class of tetraspanins (Figure 3D). This resulted in significantly decreased ANF-RFP uptake, indicating loss of filtration function (Figure 3E). We also found overt alterations in nephrocyte ultrastructure (Figure 3F), proving the importance of the tetraspanin protein class for nephrocyte function. Podocyte protein homeostasis largely depends on signaling mediated via posttranslational modifications, such as phosphorylation, ubiquitylation, acetylation, and proteolytic processing (New et al., 2014New L.A. Martin C.E. Jones N. Advances in slit diaphragm signaling.Curr. Opin. Nephrol. Hypertens. 2014; 23: 420-430Crossref PubMed Scopus (27) Google Scholar). Pinpointing podocyte-specific signaling molecules could help us to understand podocyte physiology and target podocyte signaling pharmacologically or genetically. Table 1 summarizes unanticipated observations of signaling molecules enriched in mouse podocytes; among these were several druggable molecules. (For a full list of podocyte enriched kinases, phosphatases, ubiquitin ligases, proteases, signaling receptors, actin binding proteins and transcription factors, see Table S5). We also mapped the 551 podocyte-enriched proteins against known protein interaction databases to obtain a network and central nodes among these podocyte-enriched proteins (Cerami et al., 2010Cerami E. Demir E. Schultz N. Taylor B.S. Sander C. Automated network analysis identifies core pathways in glioblastoma.PLoS ONE. 2010; 5: e8918Crossref PubMed Scopus (247) Google Scholar). The proteins RhoA, Actin, and Grb and the nephrin-regulating kinase Src had most edges within these networks (Figure S4B); all four have reported relevance for podocyte biology (Harita et al., 2008Harita Y. Kurihara H. Kosako H. Tezuka T. Sekine T. Igarashi T. Hattori S. 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.J. Biol. Chem. 2008; 283: 9177-9186Crossref PubMed Scopus (52) Google Scholar, New et al., 2014New L.A. Martin C.E. Jones N. Advances in slit diaphragm signaling.Curr. Opin. Nephrol. Hypertens. 2014; 23: 420-430Crossref PubMed Scopus (27) Google Scholar, Schmieder et al., 2004Schmieder S. Nagai M. Orlando R.A. Takeda T. Farquhar M.G. Podocalyxin activates RhoA and induces actin reorganization through NHERF1 and Ezrin in MDCK cells.J. Am. Soc. Nephrol. 2004; 15: 2289-2298Crossref PubMed Scopus (98) Google Scholar), suggesting a central role for these proteins.Table 1Examples of Podocyte-Enriched Kinases, Transcription Factors, and Potentially Druggable TargetsGene SymbolUniprot IDLog2(Ratio), (−log(p))NameCommentReferencesCsnk1g3Q8C4X22.14 (2.84)casein kinase 1 gamma 3an acidophilic S/T protein kinase that is a candidate for abundant acidophilic phosphorylation on slit diaphragm proteins (Nephrin, Trpc6, and Cd2ap)Rinschen et al., 2014Rinschen M.M. Wu X. König T. Pisitkun T. Hagmann H. Pahmeyer C. Lamkemeyer T. Kohli P. Schnell N. Schermer B. et al.Phosphoproteomic Analysis Reveals Regulatory Mechanisms at the Kidney Filtration Barrier.J. Am. Soc. Nephrol. 2014; 25: 1509-1522Crossref PubMed Scopus (31) Google Scholar, Rinschen et al., 2015bRinschen M.M. Pahmeyer C. Pisitkun T. Schnell N. Wu X. Maaß M. Bartram M.P. Lamkemeyer T. Schermer B. Benzing T. et al.Comparative phosphoproteomic analysis of mammalian glomeruli reveals conserved podocin C-terminal phosphorylation as a determinant of slit diaphragm complex architecture.Proteomics. 2015; 15: 1326-1331Crossref PubMed Scopus (18) Google ScholarNek1B7ZWK03.43 (3.61)serine/threonine protein kinase Nek1a protein kinase (STY) responsible for ciliogenesisShalom et al., 2008Shalom O. Shalva N. Altschuler Y. Motro B. The mammalian Nek1 kinase is involved in primary cilium formation.FEBS Lett. 2008; 582: 1465-1470Crossref PubMed Scopus (65) Google ScholarMst4Q99JT2;2.89 (4.70)serine/threonine protein kinase MST4members of the canonical hippo pathway, linked to mechanotransduction and apoptosis, druggableSchwartzman et al., 2015Schwartzman M. Reginensi A. Wong J.S. Basgen J.M. Meliambro K. Nicholas S.B. D’Agati V. McNeill H. Campbell K.N. Podocyte-Specific Deletion of Yes-Associated Protein Causes FSGS and Progressive Renal Failure.J. Am. Soc. Nephrol. 2015; 27: 216-226Crossref PubMed Scopus (50) Google Scholar, Rinschen et al., 2017Rinschen M.M. Grahammer F. Hoppe A.-K. Kohli P. Hagmann H. Kretz O. Bertsch S. Höhne M. Göbel H. Bartram M.P. et al.YAP-mediated mechanotransduction determines the podocyte’s response to damage.Sci. Signal. 2017; 10 (eaaf8165)Crossref PubMed Scopus (35) Google ScholarLats2Q7TSJ63.25 (2.37)serine/threonine protein kinase LATS2Tead1P300513.70 [1.83]transcriptional enhancer factor TEF-1Dach1Q9QYB24.63 (4.22)dachshund homolog 1a transcription factor strongly enriched in podocytes (comparable with WT1), GWAS demonstrate association with GFRKöttgen et al., 2010Köttgen A. Pattaro C. Böger C.A. Fuchsberger C. Olden M. Glazer N.L. Parsa A. Gao X. Yang Q. Smith A.V. et al.New loci associated with kidney function and chronic kidney disease.Nat. Genet. 2010; 42: 376-384Crossref PubMed Scopus (572) Google ScholarCblbB9EKI5;Q3TTA74.10 (2.23)E3 ubiquitin-protein ligase CBL-Bstrongest enriched ubiquitin ligase in podocytes, localizes in immune cells and mediates the expression of EGF receptors in a protein complex with the recently discovered podocin-associated ubiquitin ligase Ubr4, potentially druggableRinschen et al., 2016aRinschen M.M. Bharill P. Wu X. Kohli P. Reinert M.J. Kretz O. Saez I. Schermer B. Höhne M. Bartram M.P. et al.The ubiquitin ligase Ubr4 controls stability of podocin/MEC-2 supercomplexes.Hum. Mol. Genet. 2016; 25: 1328-1344Crossref PubMed Scopus (32) Google Scholar, Tong et al., 2014Tong J. Taylor P. Moran M.F. Proteomic analysis of the epidermal growth factor receptor (EGFR) interactome and post-translational modifications associated with receptor endocytosis in response to EGF and stress.Mol. Cell. Proteomics MCP. 2014; 13: 1644-1658Crossref PubMed Scopus (58) Google Scholar, Wirnsberger et al., 2016Wirnsberger G. Zwolanek F. Asaoka T. Kozieradzki I. Tortola L. Wimmer R.A. Kavirayani A. Fresser F. Baier G. Langdon W.Y. et al.Inhibition of CBLB protects from lethal Candida albicans sepsis.Nat. Med. 2016; 22: 915-923Crossref PubMed Scopus (59) Google ScholarNpr3P701804.89 (1.89)atrial natriuretic peptide receptor 3mediates ANP signaling via cGMP, confirmation of in vitro and in vivo studiesRinschen et al., 2016bRinschen M.M. Schroeter C.B. Koehler S. Ising C. Schermer B. Kann M. Benzing T. Brinkkoetter P.T. Quantitative deep-mapping of the cultured podocyte proteome uncovers shifts in proteostatic mechanisms during differentiation.Am. J. Physiol. Cell Physiol. 2016; 311: C404-C417Crossref PubMed Scopus (21) Google Scholar, Staffel et al., 2016Staffel J. Valletta D. Federlein A. Ehm K. Volkmann R. Füchsl A.M. Witzgall R. Kuhn M. Schweda F. Natriuretic Peptide Receptor Guanylyl Cyclase-A in Podocytes is Renoprotective but Dispensable for Physiologic Renal Function.J. Am. Soc. Nephrol. 2016; 28: 260-277Crossref PubMed Scopus (14) Google ScholarNpr1P182932.38 (3.70)atrial natriuretic peptide receptor 1Pth1rP415936.19 (2.78)PTH receptormediates Pth signaling via cAMP, confirmation of in vitro studiesEndlich and Endlich, 2002Endlich N. Endlich K. cAMP pathway in podocytes.Microsc. Res. Tech. 2002; 57: 228-231Crossref PubMed Scopus (28) Google ScholarIfngr1P152613.85 (1.86)interferon gamma receptor 1confirmation of in vitro and in vivo study, druggableGurkan et al., 2013Gurkan S. Cabinian A. Lopez V. Bhaumik M. Chang J.-M. Rabson A.B. Mundel P. Inhibition of type I interferon signalling prevents TLR ligand-mediated proteinuria.J. Pathol. 2013; 231: 248-256Crossref PubMed Scopus (18) Google ScholarMertkQ608054.83 (4.36)tyrosine protein kinase Mermost enriched tyrosine kinase family, involved in cancer and development, druggableLee-Sherick et al., 2015Lee-Sherick A.B. Zhang W. Menachof K.K. Hill A.A. Rinella S. Kirkpatrick G. Page L.S. Stashko M.A. Jordan C.T. Wei Q. et al.Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia.Oncotarget. 2015; 6: 6722-6736Crossref PubMed Scopus (30) Google Scholar, Zhang et al., 2014Zhang W. DeRyckere D. Hunter D. Liu J. Stashko M.A. Minson K.A. Cummings C.T. Lee M. Glaros T.G. Newton D.L. et al.UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor.J. Med. Chem. 2014; 57: 7031-7041Crossref PubMed Scopus (76) Google Scholar, Fleuren et al., 2014Fleuren E.D.G. Hillebrandt-Roeffen M.H.S. Flucke U.E. Te Loo D.M.W.M. Boerman O.C. van der Graaf W.T.A. Versleijen-Jonkers Y.M.H. The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma.Oncotarget. 2014; 5: 12753-12768Crossref PubMed Scopus (34) Google ScholarTyro3P551444.30 (3.76)tyrosine protein kinase receptor TYRO3AxlQ6PE804.02 (3.32)Tyrosine-protein kinase receptor UFOLog2(Ratio) is defined as log2(LFQ in podocytes)/(LFQ in non-podocytes) and is a measurement of podocyte enrichment. Table S5 gives an overview of each class of the annotated signaling molecules. GWAS, genome-wide association study; EGF, epidermal growth factor; cAMP, cyclic AMP; GFR, glomerular filtration rate; cGMP, cyclic GMP; PTH, parathyroid hormone; atrial natriuretic peptide (ANP). Open table in a new tab Log2(Ratio) is defined as log2(LFQ in podocytes)/(LFQ in non-podocytes) and is a measurement of podocyte enrichment. Table S5 gives an overview of each class of the annotated signaling molecules. GWAS, genome-wide association study; EGF, epidermal growth factor; cAMP, cyclic AMP; GFR, glomerular filtration rate; cGMP, cyclic GMP; PTH, parathyroid hormone; atrial natriuretic peptide (ANP). We asked whether this unique obtained podocyte proteome resource wo" @default.
• W2803593737 created "2018-06-01" @default.
• W2803593737 creator A5004648123 @default.
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• W2803593737 date "2018-05-01" @default.
• W2803593737 modified "2023-10-15" @default.
• W2803593737 title "A Multi-layered Quantitative In Vivo Expression Atlas of the Podocyte Unravels Kidney Disease Candidate Genes" @default.
• W2803593737 cites W1497793851 @default.
• W2803593737 cites W1566478885 @default.
• W2803593737 cites W1600368247 @default.
• W2803593737 cites W1908362533 @default.
• W2803593737 cites W1931041435 @default.
• W2803593737 cites W1955394435 @default.
• W2803593737 cites W1965991024 @default.
• W2803593737 cites W1968216888 @default.
• W2803593737 cites W1969298311 @default.
• W2803593737 cites W1972399884 @default.
• W2803593737 cites W1973268693 @default.
• W2803593737 cites W1976709402 @default.
• W2803593737 cites W1978746677 @default.
• W2803593737 cites W1982281628 @default.
• W2803593737 cites W1988472236 @default.
• W2803593737 cites W1990895973 @default.
• W2803593737 cites W1998399313 @default.
• W2803593737 cites W2004754771 @default.
• W2803593737 cites W2012034410 @default.
• W2803593737 cites W2022501325 @default.
• W2803593737 cites W2029096450 @default.
• W2803593737 cites W2029952427 @default.
• W2803593737 cites W2038438556 @default.
• W2803593737 cites W2040670636 @default.
• W2803593737 cites W2048451191 @default.
• W2803593737 cites W2054035764 @default.
• W2803593737 cites W2054225562 @default.
• W2803593737 cites W2056499061 @default.
• W2803593737 cites W2058194775 @default.
• W2803593737 cites W2063770484 @default.
• W2803593737 cites W2064631610 @default.
• W2803593737 cites W2064732202 @default.
• W2803593737 cites W2069860553 @default.
• W2803593737 cites W2074397527 @default.
• W2803593737 cites W2081645165 @default.
• W2803593737 cites W2082479585 @default.
• W2803593737 cites W2085574022 @default.
• W2803593737 cites W2085743492 @default.
• W2803593737 cites W2101349818 @default.
• W2803593737 cites W2103977381 @default.
• W2803593737 cites W2104010513 @default.
• W2803593737 cites W2105257258 @default.
• W2803593737 cites W2106852912 @default.
• W2803593737 cites W2107578201 @default.
• W2803593737 cites W2110230080 @default.
• W2803593737 cites W2110625124 @default.
• W2803593737 cites W2110726109 @default.
• W2803593737 cites W2111410841 @default.
• W2803593737 cites W2112830170 @default.
• W2803593737 cites W2117729643 @default.
• W2803593737 cites W2119711419 @default.
• W2803593737 cites W2124091237 @default.
• W2803593737 cites W2128551987 @default.
• W2803593737 cites W2129416468 @default.
• W2803593737 cites W2130552692 @default.
• W2803593737 cites W2131349854 @default.
• W2803593737 cites W2139742898 @default.
• W2803593737 cites W2143795731 @default.
• W2803593737 cites W2144807905 @default.
• W2803593737 cites W2147921697 @default.
• W2803593737 cites W2148123685 @default.
• W2803593737 cites W2149336866 @default.
• W2803593737 cites W2152983548 @default.
• W2803593737 cites W2155015733 @default.
• W2803593737 cites W2160019957 @default.
• W2803593737 cites W2163605874 @default.

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