title: Nephrin Suppresses Hippo Signaling through the Adaptor Proteins Nck and WTIP.
abstract: Podocytes are key components of the kidney blood filtration barrier, and their ability to withstand hemodynamic strain is proposed to be closely tied to their unique and flexible cytoarchitecture. However, the mechanisms that control such mechanotransduction are poorly understood. We have previously established that tyrosine phosphorylation of the transmembrane protein nephrin promotes recruitment of the Nck1/2 cytoskeletal adaptor proteins and downstream actin remodeling. We now reveal that Nck integrates nephrin with the Hippo kinase cascade through association with the adaptor protein WTIP. Using mutational analysis, we show that Nck sequesters WTIP and its binding partner Lats1 to phosphorylated nephrin, resulting in decreased phospho-activation of Lats1. We further demonstrate that, coincident with nephrin dephosphorylation in a transient model of podocyte injury in mice, Lats1 is rapidly activated, and this precedes significant down-regulation of the transcription regulator Yap. Moreover, we show reduced levels of Yap protein in mice with chronic disruption of nephrin phospho-signaling. Together, these findings support the existence of a dynamic molecular link between nephrin signaling and the canonical Hippo pathway in podocytes, which may facilitate the conversion of mechanical cues to biochemical signals promoting podocyte viability.
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Ava
authors.initials: A
authors.lastname: Keyvani Chahi
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Martin
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada. Electronic address: jonesmcb@uoguelph.ca.
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D056970:Co-Repressor Proteins; D003598:Cytoskeletal Proteins; D005260:Female; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D008297:Male; D040542:Mechanotransduction, Cellular; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D050199:Podocytes / Q000378:metabolism; D060066:Protein Interaction Maps; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C485544:NCK2 protein, human; C078332:Nck protein; D015513:Oncogene Proteins; C484859:WTIP protein, human; C113267:nephrin; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; Nck; WTIP; kidney; nephrin; phosphotyrosine; podocyte; signal transduction