title: NEPH1 defines a novel family of podocin interacting proteins.
abstract: Mutations of NPHS1 or NPHS2, the genes encoding for the glomerular podocyte proteins nephrin and podocin, cause steroid-resistant proteinuria. In addition, mice lacking NEPH1 develop a nephrotic syndrome that resembles NPHS mutations, suggesting that all three proteins are essential for the integrity of glomerular podocytes. Podocin interacts with the C-terminal domain of nephrin and facilitates nephrin-dependent signaling. NEPH1, a member of the immunoglobulin superfamily, is structurally related to nephrin. We report now that NEPH1 belongs to a family of three closely related proteins that interact with the C-terminal domain of podocin. All three NEPH proteins share a conserved podocin-binding motif; mutation of a centrally located tyrosine residue dramatically lowers the affinity of NEPH1 for podocin. NEPH1 triggers AP-1 activation similarly to nephrin but requires the presence of Tec family kinases for efficient transactivation. We conclude that NEPH1 defines a new family of podocin-binding molecules that are potential candidates for hereditary nephrotic syndromes not linked to either NPHS1 or NPHS2.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University Hospital Freiburg, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Sellin
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: Peter
authors.initials: P
authors.lastname: Gerke
authors.forename: Ivo
authors.initials: I
authors.lastname: Quack
authors.forename: Hermann
authors.initials: H
authors.lastname: Pavenstädt
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000145:classification; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431137:KIRREL1 protein, human; C470936:KIRREL3 protein, human; C486606:Kirrel1 protein, mouse; D008565:Membrane Proteins; C407223:NPHS2 protein; D011506:Proteins; D018808:Transcription Factor AP-1; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases