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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

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

Worthmann Kirstin K Leitges Michael M Teng Beina B Sestu Marcello M Tossidou Irini I Samson Thomas T Haller Hermann H Huber Tobias B TB Schiffer Mario M

The American journal of pathology 20131003 6

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 ...[more]

PMID: 24096077

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Project description:The members of the atypical subfamily of protein kinase C (PKC) show dramatic structural and functional differences from other PKC isotypes. Thus, in contrast to the classical or novel PKCs, they are not activated by diacylglycerol or phorbol esters. However, the atypical PKCs are the target of important lipid second messengers such as ceramide, phosphatidic acid, and 3'-phosphoinositides. The catalytic and pseudosubstrate sequences in the two atypical PKCs (lambda/iota PKC and zeta PKC) are identical but are significantly different from those of conventional or novel PKCs. It has been shown that microinjection of a peptide with the sequence of the pseudosubstrate of the atypical PKC isotypes but not of alpha PKC or epsilon PKC dramatically inhibited maturation and NF-kappa B activation in Xenopus oocytes, as well as reinitiation of DNA synthesis in quiescent mouse fibroblasts. This indicates that either or both atypical isoforms are important in cell signalling. Besides the pseudosubstrate, the major differences in the sequence between lambda/iota PKC and zeta PKC are located in the regulatory domain. Therefore, any functional divergence between the two types of atypical PKCs will presumably reside in that region. We report here the molecular characterization of lambda-interacting protein (LIP), a novel protein that specifically interacts with the zinc finger of lambda/iota PKC but not zeta PKC. We show in this paper that this interaction is detected not only in vitro but also in vivo, that LIP activates lambda/iota PKC but not zeta PKC in vitro and in vivo, and that this interaction is functionally relevant. Thus, expression of LIP leads to the transactivation of a kappa B-dependent promoter in a manner that is dependent on lambda/iota PKC. To our knowledge, this is the first report on the cloning and characterization of a protein activator of a PKC that binds to the zinc finger domain, which has so far been considered a site for binding of lipid modulators. The fact that LIP binds to lambda/iota PKC but not to the highly related zeta PKC isoform suggests that the specificity of the activation of the members of the different PKC subfamilies will most probably be accounted for by proteins like LIP rather than by lipid activators.

Dataset Information

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

Publications

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

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