Diacylglycerol Signaling

10 Atypical PKCs, NF-kB, and Inflammation
implicated in the control of cell polarity in C. elegans and Drosophila (Macara
2004; Ohno 2001). Although genetic data has yet to be produced to prove the role
of the aPKCs and Par-6 in different aspects of mammalian cell polarity, overexpression
analyses have implicated the Par-6/aPKC complex in the control of the
epithelial–mesenchymal transition (Ozdamar et al. 2005), T cell (Ludford-Menting
et al. 2005) and neuronal polarity (Shi et al. 2003), and cell polarity in migrating
astrocytes (Etienne-Manneville and Hall 2003), among other functions. Therefore,
the formation of aPKC complexes with different adapters and scaffold proteins
serves to confer specificity and plasticity to the actions of these kinases.
The mechanistic link between p62 and NF-kB received further support when it
was shown that TRAF6 interacts with p62 (Sanz et al. 2000). This is particularly
relevant because TRAF6 is an important intermediary in the IL-1, NGF, and LPS
signaling pathways controlling NF-kB through still not totally clarified mechanisms
likely involving K-63 ubiquitination of IKKg (Sun et al. 2004). Ref(2)P
interacts not only with Drosophila PKCz, but also with the fly homologue of
TRAF6 (dTRAF2), again reinforcing the conservation of function in this pathway
(Avila et al. 2002). In mammalian cells p62 also interacts with RIP, which mediates
NF-kB activation in response to TNFa (Sanz et al. 1999). Both interactions seem
to be physiologically relevant since downregulation of p62 levels with antisense
constructs leads to a significant reduction of NF-kB activation in IL-1 or TNFaactivated
cells. In vivo experiments using p62-deficient mice show a clear impairment
in osteoclastogenesis in response to injections of the calciotropic hormone
PTHrP. Also, osteoclast precursors from p62−/− mice respond poorly to RANK-L
in cell cultures, and are unable to produce a sustained NF-kB response (Duran
et al. 2004b). This suggests that p62 can be considered essential in the control of
osteoclastogenesis and bone remodeling. Whether this is due to its ability to interact
with the aPKCs or whether it is related to the preferential binding of p62 to K63linked
ubiquitinated proteins is a matter for future research. Nonetheless, these
observations highlight the importance of specificity during cell signaling through
specific adapters that serve to restrict a kinase’s action, but that simultaneously
allow enough crosstalk between pathways to regulate complex biological events
such as inflammation.
Of note, p62 has been shown to be required for the sustained phase of NF-kB
activation during T-cell differentiation, a process that is critical in asthma and
other allergic diseases (Martin et al. 2006). Interestingly, as in osteoclasts, p62
levels are induced upon T cell differentiation (Martin et al. 2006), suggesting
that p62 is necessary to control biochemical events required for proper differentiation
in different cell systems. The loss of p62 in T cells impairs their ability
to produce Th2 cytokines ex vivo, but the activation of the IL-4/Jak1/Stat6 cascade
was not affected by the loss of p62 (Martin et al. 2006). In addition, experiments
using the OVA-induced allergic airway inflammation model clearly
demonstrated that p62 is required for an optimal lung inflammatory response
(Martin et al. 2006). Therefore, p62, like PKCz, emerges as an important component
of the signaling cascades regulating Th2 function and asthma, but acting
through a different mechanism.
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