Neph-Nephrin proteins bind the Par3-Par6-atypical protein kinase C (aPKC) complex to regulate podocyte cell polarity.
The kidney filter represents a unique assembly of podocyte epithelial cells that tightly enwrap the glomerular capillaries with their foot processes and the interposed slit diaphragm. So far, very little is known about the guidance cues and polarity signals required to regulate proper development and maintenance of the glomerular filtration barrier. We now identify Par3, Par6, and atypical protein kinase C (aPKC) polarity proteins as novel Neph1-Nephrin-associated proteins. The interaction was mediated through the PDZ domain of Par3 and conserved carboxyl terminal residues in Neph1 and Nephrin. Par3, Par6, and aPKC localized to the slit diaphragm as shown in immunofluorescence and immunoelectron microscopy. Consistent with a critical role for aPKC activity in podocytes, inhibition of glomerular aPKC activity with a pseudosubstrate inhibitor resulted in a loss of regular podocyte foot process architecture. These data provide an important link between cell recognition mediated through the Neph1-Nephrin complex and Par-dependent polarity signaling and suggest that this molecular interaction is essential for establishing the three-dimensional architecture of podocytes at the kidney filtration barrier.
Hartleben
Björn
B
Renal Division, University Hospital Freiburg, D-79106 Freiburg, Germany.
Schweizer
Heiko
H
Lübben
Pauline
P
Bartram
Malte P
MP
Möller
Clemens C
CC
Herr
Ronja
R
Wei
Changli
C
Neumann-Haefelin
Elke
E
Schermer
Bernhard
B
Zentgraf
Hanswalter
H
Kerjaschki
Dontscho
D
Reiser
Jochen
J
Walz
Gerd
G
Benzing
Thomas
T
Huber
Tobias B
TB
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry*; D018797:Cell Cycle Proteins / Q000737:chemistry*; D016764:Cell Polarity; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000166:cytology*; D011493:Protein Kinase C / Q000737:chemistry*
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; C431137:KIRREL1 protein, human; C486606:Kirrel1 protein, mouse; D008565:Membrane Proteins; C509689:PARD3 protein, human; C499657:PARD6A protein, human; C518597:Par6 protein, mouse; C115084:Pard3 protein, mouse; C113267:nephrin; C115015:PKC-3 protein; D011493:Protein Kinase C