DAG signaling taught us a lesson: what diverges can converge

One of the most intriguing and complex issues in signal transduction relates to convergence-divergence of the receptor-effector coupling and second messenger function. Tyrosine kinase and 7 transmembrane receptors couple to multiple effectors to elicit a broad spectrum of signaling events. Diacylglycerol (DAG) is one of the crucial lipid second messengers generated upon receptor activation, since it activates several members of the protein kinase C (PKC) family, serine-threonine kinases that control essential functions such as the cell cycle, death and survival, and differentiation. However, the narrow concept that all DAG signals proceed through PKC has been disputed by the discovery of novel targets for this lipid second messenger, which may lead to divergence of DAG signaling through PKC-independent pathways. The discovery of the Ras exchange factor RasGRP1 by Stone and coworkers in 1998 (Science. 1998:280;1082-1086) as a new DAG target and the determination of its role in T-cell receptor (TCR) coupling to the Ras–mitogen-activated protein kinase (MAPK) cascade represented one of the major breakthroughs in a field that had been quite dogmatic by assuming that PKC does it all.

Again, Stone and coworkers raised a new flag: DAG targets “talk” to each other, providing an additional level of regulation and integration in diversity. On page 1414 of this issue of Blood, Teixeira and colleagues show that RasGRP3, a RasGRP isoform selectively expressed in B cells, can be regulated by PKC upon stimulation with a phorbol ester or stimulation of the B-cell receptor (BCR). Phosphorylation of RasGRP3 by PKC may be critical to modulate its association with Ras at the plasma membrane and the subsequent activation of the ERK MAPK cascade. Whether only a single PKC isozyme is involved in the effect still needs to be clarified. Since the PKCβ knockout mice have a defect in B-cell development, one may expect that this PKC isozyme represents a key player. Indeed, the data provided in this paper show that RasGRP3 is a PKCβ substrate.

Elucidation of these complex signaling mechanisms is essential, since several PKC modulators are being tested in clinical trials for hemopoietic cancers. The evidence that DAG is essential in BCR and TCR signaling is compelling. Moreover, additional targets for DAG have been isolated, and molecules like the chimaerin Rac-GAPs and the diacylglycerol kinases (DGKs) could represent additional points of divergence. The seminal work on RasGRPs presented by the laboratory of Jim Stone taught us a lesson: DAG signals that diverge can also converge. Isn't this the time to start talking about integration?