Format

Send to

Choose Destination
Am J Pathol. 2013 Dec;183(6):1945-1959. doi: 10.1016/j.ajpath.2013.08.026. Epub 2013 Oct 3.

Def-6, a novel regulator of small GTPases in podocytes, acts downstream of atypical protein kinase C (aPKC) λ/ι.

Author information

1
Division of Nephrology, Department of Medicine, Hannover Medical School, Hannover, Germany.
2
Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.
3
Faculty of Medicine, Interdisciplinary Centre for Clinical Research (IZKF) Leipzig, University of Leipzig, Leipzig, Germany.
4
Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
5
Renal Division, University Hospital Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany.
6
Division of Nephrology, Department of Medicine, Hannover Medical School, Hannover, Germany. Electronic address: schiffer.mario@mh-hannover.de.

Abstract

The atypical protein kinase C (aPKC) isotypes PKCλ/ι and PKCζ are both expressed in podocytes; however, little is known about differences in their function. Previous studies in mice have demonstrated that podocyte-specific loss of PKCλ/ι leads to a severe glomerular phenotype, whereas mice deficient in PKCζ develop no renal phenotype. We analyzed various effects caused by PKCλ/ι and PKCζ deficiency in cultured murine podocytes. In contrast to PKCζ-deficient podocytes, PKCλ/ι-deficient podocytes exhibited a severe actin cytoskeletal phenotype, reduced cell size, decreased number of focal adhesions, and increased activation of small GTPases. Comparative microarray analysis revealed that the guanine nucleotide exchange factor Def-6 was specifically up-regulated in PKCλ/ι-deficient podocytes. In vivo Def-6 expression is significantly increased in podocytes of PKCλ/ι-deficient mice. Cultured PKCλ/ι-deficient podocytes exhibited an enhanced membrane association of Def-6, indicating enhanced activation. Overexpression of aPKCλ/ι in PKCλ/ι-deficient podocytes could reduce the membrane-associated expression of Def-6 and rescue the actin phenotype. In the present study, PKCλ/ι was identified as an important factor for actin cytoskeletal regulation in podocytes and Def-6 as a specific downstream target of PKCλ/ι that regulates the activity of small GTPases and subsequently the actin cytoskeleton of podocytes.

PMID:
24096077
PMCID:
PMC5707189
DOI:
10.1016/j.ajpath.2013.08.026
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center