NEPH1 defines a novel family of podocin interacting proteins

FASEB J. 2003 Jan;17(1):115-7. doi: 10.1096/fj.02-0242fje. Epub 2002 Nov 1.


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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Cell Line
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kidney / cytology
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Mice
  • Models, Biological
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / classification
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • KIRREL1 protein, human
  • KIRREL3 protein, human
  • Kirrel1 protein, mouse
  • Membrane Proteins
  • NPHS2 protein
  • Proteins
  • Transcription Factor AP-1
  • Tec protein-tyrosine kinase
  • Protein-Tyrosine Kinases