An old kinase on a new path: Raf and apoptosis

The cytosolic serine/threonine Raf kinases play a central role in evolutionary conserved signal transduction pathways. An impressive number of publications implicates these enzymes in a variety of biological processes, most prominently in regulated and deregulated proliferation. Because of this, they are considered attractive therapeutic targets. Gene ablation experiments have now revealed that in the context of the mouse embryo Raf-1 and B-Raf play essential anti-apoptotic roles that cannot be rescued by the other Raf isoforms. In the case of Raf-1 it is clear that its best-studied downstream target, the MEK/ERK pathway, does not mediate the anti-apoptotic function of the kinase. These experiments have shed new light on the biological role of the Raf kinases and have prompted a search for alternative substrates mediating it.

Raf is a family of three serine/threonine specific kinases (A-Raf, B-Raf, and Raf-1) ubiquitously expressed throughout embryonic development.¹ All three enzymes can be activated by the small G protein Ras and relay upstream input signals to the MEK/ERK module. Activated ERK controls an impressive roster of substrates, ranging from metabolic enzymes to specific transcription factors whose phosphorylation affects the pattern of gene expression. Within this signaling cascade, Raf interacts physically with MEK-1 via its kinase domain and with GTP-loaded Ras via its N-terminus. The high affinity binding to activated Ras mediates the translocation of Raf-1 from the cytosol to the plasma membrane, where activation occurs via a complex, yet incompletely defined mechanism involving phosphorylation and dephosphorylation.² Both Ras and Raf are proto-oncogenes, and deregulation of the ERK pathway is involved in the pathogenesis of severe diseases that affect large portions of the population. Specifically, the ERK pathway is deregulated in more than 30% of common cancers. Therefore, the Raf kinases are an attractive target for novel therapies aimed at interfering with its activation process and at eventually reversing its deregulated functions.

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