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

QC 20121210
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 a-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.

Lal, Mark (author)
Hulkko, Jenny (author)
Hultenby, KjellKarolinska Institutet (author)
Önfelt, BjörnKarolinska Institutet,KTH,Cellens fysik(Swepub:kth)u1tquq43 (author)
Sun, Ying (author)
Dunér, FredrikKarolinska Institutet (author)
Patrakka, JaakkoKarolinska Institutet (author)
Betsholtz, ChristerKarolinska Institutet (author)
Uhlén, MathiasKTH,Proteomik(Swepub:kth)u1dulvmw (author)
Brismar, HjalmarKarolinska Institutet,KTH,Cellens fysik(Swepub:kth)u1232ew5 (author)
Tryggvason, KarlKarolinska Institutet (author)
Wernerson, AnnikaKarolinska Institutet (author)
Pikkarainen, Timo (author)
Karolinska InstitutetCellens fysik (creator_code:org_t)

By the author/editor: Perisic, Ljubica; Lal, Mark; Hulkko, Jenny; Hultenby, Kjell; Önfelt, Björn; Sun, Ying; show more...; Dunér, Fredrik; Patrakka, Jaakko; Betsholtz, Chris ...; Uhlén, Mathias; Brismar, Hjalmar; Tryggvason, Karl; Wernerson, Annik ...; Pikkarainen, Tim ...; show less...

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