title: Yes-associated protein (YAP) promotes cell survival by inhibiting proapoptotic dendrin signaling.
abstract: Kidney podocytes are highly specialized terminally differentiated cells that form the final barrier to urinary protein loss. Podocytes are a target for injury by metabolic, autoimmune, hereditary, inflammatory, and other stressors. Persistence of podocyte injury leads to podocyte death and loss, which results in progressive kidney damage and ultimately kidney failure. Dendrin is a dual compartment protein with proapoptotic signaling properties. Nuclear relocation of dendrin in response to glomerular injury promotes podocyte apoptosis. Here we show that Yes-associated protein (YAP), a downstream target of Hippo kinases and an inhibitor of apoptosis, is expressed in the nucleus of podocytes. The WW domains of YAP mediate the interaction with the PPXY motifs of dendrin. This interaction is functionally relevant because YAP binding to dendrin reduces dendrin-dependent, staurosporine-induced apoptosis in co-transfected HEK293 cells. Moreover gene silencing of YAP in podocytes increases adriamycin-induced podocyte apoptosis. It also increases staurosporine-induced caspase-3/7 activity, which is rescued by dendrin depletion in YAP knockdown cells. Our findings elucidate YAP binding to dendrin as a prosurvival mechanism. The antiapoptotic signaling properties of YAP in podocytes could hold significance in the quest for targeted therapeutics aimed at preventing podocyte loss.
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, New York 10029, USA. kirk.campbell@mssm.edu
authors.forename: Kirk N
authors.initials: KN
authors.lastname: Campbell
authors.forename: Jenny S
authors.initials: JS
authors.lastname: Wong
authors.forename: Ritu
authors.initials: R
authors.lastname: Gupta
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Asanuma
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors; D020798:Two-Hybrid System Techniques; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C104328:dendrin; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7
keywords: Apoptosis; Caspase; Cell Death; Kidney; Podocytes