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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.

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


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.

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