Plekhh2, a novel podocyte protein downregulated in human focal segmental glomerulosclerosis, is involved in matrix adhesion and actin dynamics

Kidney Int. 2012 Nov;82(10):1071-83. doi: 10.1038/ki.2012.252. Epub 2012 Jul 25.


Pleckstrin homology domain-containing, family H (with MyTH4 domain), member 2 (Plekhh2) is a 1491-residue intracellular protein highly enriched in renal glomerular podocytes for which no function has been ascribed. Analysis of renal biopsies from patients with focal segmental glomerulosclerosis revealed a significant reduction in total podocyte Plekhh2 expression compared to controls. Sequence analysis indicated a putative α-helical coiled-coil segment as the only recognizable domain within the N-terminal half of the polypeptide, while the C-terminal half contains two PH, a MyTH4, and a FERM domain. We identified a phosphatidylinositol-3-phosphate consensus-binding site in the PH1 domain required for Plekhh2 localization to peripheral regions of cell lamellipodia. The N-terminal half of Plekkh2 is not necessary for lamellipodial targeting but mediates self-association. Yeast two-hybrid screening showed that Plekhh2 directly interacts through its FERM domain with the focal adhesion protein Hic-5 and actin. Plekhh2 and Hic-5 coprecipitated and colocalized at the soles of podocyte foot processes in situ and Hic-5 partially relocated from focal adhesions to lamellipodia in Plekhh2-expressing podocytes. In addition, Plekhh2 stabilizes the cortical actin cytoskeleton by attenuating actin depolymerization. Our findings suggest a structural and functional role for Plekhh2 in the podocyte foot processes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Actin Cytoskeleton / pathology
  • Actins / metabolism*
  • Animals
  • Binding Sites
  • Biopsy
  • CHO Cells
  • COS Cells
  • Case-Control Studies
  • Cell-Matrix Junctions / metabolism*
  • Chlorocebus aethiops
  • Cricetinae
  • Cricetulus
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Glomerulosclerosis, Focal Segmental / genetics
  • Glomerulosclerosis, Focal Segmental / metabolism*
  • Glomerulosclerosis, Focal Segmental / pathology
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • LIM Domain Proteins / metabolism
  • Mice
  • Phosphatidylinositol Phosphates / metabolism
  • Podocytes / metabolism*
  • Podocytes / pathology
  • Protein Interaction Domains and Motifs
  • Protein Interaction Mapping
  • Protein Structure, Secondary
  • Protein Transport
  • Pseudopodia / metabolism
  • Sequence Analysis, Protein
  • Transfection
  • Two-Hybrid System Techniques


  • Actins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Phosphatidylinositol Phosphates
  • TGFB1I1 protein, human
  • Tgfb1i1 protein, mouse
  • phosphatidylinositol 3-phosphate
  • plekhh2 protein, human
  • plekhh2 protein, mouse