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

ABSTRACT: The atypical protein kinase C (aPKC) isotypes PKC?/? and PKC? 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 PKC?/? leads to a severe glomerular phenotype, whereas mice deficient in PKC? develop no renal phenotype. We analyzed various effects caused by PKC?/? and PKC? deficiency in cultured murine podocytes. In contrast to PKC?-deficient podocytes, PKC?/?-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 PKC?/?-deficient podocytes. In vivo Def-6 expression is significantly increased in podocytes of PKC?/?-deficient mice. Cultured PKC?/?-deficient podocytes exhibited an enhanced membrane association of Def-6, indicating enhanced activation. Overexpression of aPKC?/? in PKC?/?-deficient podocytes could reduce the membrane-associated expression of Def-6 and rescue the actin phenotype. In the present study, PKC?/? was identified as an important factor for actin cytoskeletal regulation in podocytes and Def-6 as a specific downstream target of PKC?/? that regulates the activity of small GTPases and subsequently the actin cytoskeleton of podocytes.

SUBMITTER: Worthmann K 

PROVIDER: S-EPMC5707189 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature