Diacylglycerol kinases as sources of phosphatidic acid

Abstract

There are ten mammalian diacylglycerol kinases (DGKs) whose primary role is to terminate diacylglycerol (DAG) signaling. However, it is becoming increasingly apparent that DGKs also influence signaling events through their product, phosphatidic acid (PA). They do so in some cases by associating with proteins and then modifying their activity by generating PA. In other cases, DGKs broadly regulate signaling events by virtue of their ability to provide PA for the synthesis of phosphatidylinositols (PtdIns).

Fig. 1

Stucture of mammalian DGK isoforms. The ten members of the mammalian DGK family are grouped by sequence homology into five subtypes. Shown are protein motifs common to several DGKs. The significance of several of these motifs is discussed in the text. Additional motifs of uncertain significance are not shown.

Fig. 2

Model of compartmentalized DGK function. Evidence indicates that DGKs bind and influence the activity of proteins regulated by either DAG or PA. In the left panel, a DGK binds and inhibits a DAG-activated protein. In the right panel, a DGK binds a protein and, by generating PA, increases its function.

Fig. 3

Hypothetical model in which DGKζ could negatively regulate 7TMR signaling. Upon activation of the 7TMR, β-arrestin is recruited to the receptor along with its bound DGKζ. The DGK terminates DAG signaling by converting this lipid to PA. The PA, in turn, might serve to activate a PtdIns4P 5-kinase (PI5K), which generates PtdIns(4,5)P₂. This lipid promotes internalization of the 7TMR to limit access to its ligand.

Fig. 4

A simplified diagram of the PtdIns cycle. Shown are lipids that are components of the PtdIns cycle and enzymes in this cycle that are relevant to the discussion in the text.