Signaling at the membrane interface by the DGK/SK enzyme family

Daniel M Raben,Binks W Wattenberg

doi:10.1194/jlr.r800071-jlr200

Abstract

The sphingosine (SK) and diacylglycerol (DGK) kinases have become the subject of considerable focus recently due to their involvement as signaling enzymes in a variety of important biological processes. These lipid signaling kinases are closely related by sequence as well as functional properties. These enzymes are soluble, yet their substrates are hydrophobic. Therefore, they must act at the membrane interface. Second, for both of these enzyme families, their substrates (diacylglycerol for DGKs, sphingosine for SKs) as well as their products (phosphatidic acid for DGK, sphingosine-1-phosphate for SK) have signaling function. To understand how the signaling processes emanating from these kinases are regulated it is critical to understand the fundamental mechanisms that control their enzymatic activity. This is particularly true for the rational design of small molecules that would be useful as therapeutic compounds. Here we summarize enzymological properties of the diacylglycerol and SKs. Further, because the three-dimensional structure of the eukaryotic members of this family has yet to be determined, we discuss what can be gleaned from the recently reported structures of related prokaryotic members of this enzyme family.

Highlights

The sphingosine (SK) and diacylglycerol (DGK) kinases have become the subject of considerable focus recently due to their involvement as signaling enzymes in a variety of important biological processes
We discuss the structure of two prokaryotic enzymes, DgkB from Staphylococcus aureus and YegS from Salmonella, with significant homology to the eukaryotic diacylglycerol kinase (DGK) and spingosine kinase (SK)
One elegant study directly tested the role of PA to activate SK in a physiological setting using manipulation of phospholipase D (PLD) to generate phosphatidic acid in cells [9]

Summary

ACTIVATION BY LIPIDS

Acidic phospholipids enhance the activity of SKs in vitro. Phosphatidylserine (PS) and PA appear to be the most relevant lipids for SK 1, phosphatidylinositol may stimulate activity [7]. One elegant study directly tested the role of PA to activate SK in a physiological setting using manipulation of phospholipase D (PLD) to generate phosphatidic acid in cells [9] These workers demonstrated that ectopic expression of PLD leads to SK translocation to perinuclear sites where PLD is concentrated. Blocking PA production with butanol prevented agonist-dependent Fc receptor activation induced SK membrane translocation [9] This involvement of PA stands in contrast to direct biophysical measurements of SK-1 binding to lipid surfaces [10]. Similar to the SKs, a number of membrane lipids have been shown to modulate DGK activity their physiological relevance is uncertain. C1A domains of DGK-g and DGK-b bind phorbol ester [14, 15] Complicating these results, DGK-a does not translocate to the plasma membrane in response to PMA and intact DGK-g and DGK-b failed to bind this molecule. This, along with the PAinduced activation of DGK-u mentioned above, may help account for the transient nature of induced DAG production when this isoform is present

ACTIVATION BY CALCIUM AND PHOSPHORYLATION

STRUCTURAL PREDICTIONS FROM PROKARYOTIC HOMOLOGS

SUMMARY