Protein kinase C and phospholipase D: intimate interactions in intracellular signaling

Abstract

Diacylglycerol (DAG) was discovered as a potent lipid second messenger with protein kinase C (PKC) as its major cellular target more than 25 years ago. There is increasing evidence of significant complexity within lipid signaling, and the classical DAG-PKC model no longer stands alone but is part of a larger bioactive lipid universe involving glycerolipids and sphingolipids. Multiple layers of regulation exist among PKC- and DAG-metabolizing enzymes such as phosphatidylcholine (PC)-specific phospholipase D, and cross-talk exists between the glycerolipid and sphingolipid pathways, with PKC at the center. Currently, there is intense interest in the question of whether DAG derived from PC can function as a lipid second messenger and regulate PKC analogous to DAG derived from phosphatidylinositol-4,5-bisphosphate (PIP2). To address these issues and incorporate DAG-PKC and other signaling pathways into an expanded view of cell biology, it will be necessary to go beyond the classical approaches and concepts.

Interruption of Inositol Sphingolipid Synthesis Triggers Stt4p-dependent Protein Kinase C Signaling

“…Moreover, DAG produced by complex sphingolipid metabolism has been shown to activate PKC in the pathogenic fungi Cryptococcus neoformans (74). Conversely, ceramides, which are immediate precursors and turnover products of complex sphingolipid metabolism, inhibit PKC activation in mammals (75,76). However, because DAG levels are expected to decrease and ceramide levels are expected to increase when complex sphingolipid synthesis is inhibited during inositol starvation, neither DAG nor ceramides are likely to significantly contribute to PKC activity under this growth condition.…”

Chapter 3 New Insights on Mast Cell Activation via the High Affinity Receptor for IgE

“…The generation of lipid second messengers has long been recognized to be important in the effector function of mast cells as well as in other cell types (Becker and Hannun, 2005;Rivera and Olivera, 2007;Spiegel, Foster and Kolesnick, 1996). The recent advances have clearly demonstrated that lipid messengers can be dominant in certain signaling pathways and cause cellular responses independent of many of the additional events initiated by FcεRI activation.…”

Isoform Specificity of PKC Translocation in LivingAplysiaSensory Neurons and a Role for Ca2+-Dependent PKC APL I in the Induction of Intermediate-Term Facilitation

“…However, phospholipase C activity should also produce IP-3 that releases calcium from internal stores, and 5-HT does not increase resting calcium levels in sensory neurons, whereas injected IP 3 does (Blumenfeld et al, 1990). Alternatively, it is possible that 5-HT activates phospholipase D, producing phosphatidic acid, which is then converted to DAG (Becker and Hannun, 2005); in this case, IP 3 is not produced. The failure of Apl II to translocate in motor neurons is most simply explained by the lack of a 5-HT GPCR coupled to DAG production.…”