title: Plekhh2, a novel podocyte protein downregulated in human focal segmental glomerulosclerosis, is involved in matrix adhesion and actin dynamics.
abstract: 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.
authors: Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Ljubica
authors: L
authors: Perisic
authors: Mark
authors: M
authors: Lal
authors: Jenny
authors: J
authors: Hulkko
authors: Kjell
authors: K
authors: Hultenby
authors: Björn
authors: B
authors: Önfelt
authors: Ying
authors: Y
authors: Sun
authors: Fredrik
authors: F
authors: Dunér
authors: Jaakko
authors: J
authors: Patrakka
authors: Christer
authors: C
authors: Betsholtz
authors: Mathias
authors: M
authors: Uhlen
authors: Hjalmar
authors: H
authors: Brismar
authors: Karl
authors: K
authors: Tryggvason
authors: Annika
authors: A
authors: Wernerson
authors: Timo
authors: T
authors: Pikkarainen
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001706:Biopsy; D016466:CHO Cells; D019556:COS Cells; D016022:Case-Control Studies; D021982:Cell-Matrix Junctions / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000378:metabolism; D051379:Mice; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D020539:Sequence Analysis, Protein; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D018129:Phosphatidylinositol Phosphates; C490351:TGFB1I1 protein, human; C090090:Tgfb1i1 protein, mouse; C055525:phosphatidylinositol 3-phosphate; C580984:plekhh2 protein, human; C521226:plekhh2 protein, mouse