The signals that regulate cell division, differentiation and death are initiated at the plasma membrane—for example, through the binding of a ligand to its receptor—and must somehow be transmitted to target molecules within the cell interior. The addition of phosphate groups to proteins (phosphorylation), is one important way in which signals from the cell surface are transmitted within the cell. A family of serine-threonine protein kinases called MAPKs (mitogen-activated protein kinases) that phosphorylate many cytoplasmic and nuclear target proteins are crucial regulators of the cellular responses induced by many extracellular stimuli (both mitogenic and nonmitogenic). For example, MAPKs directly phosphorylate and activate a number of transcription factors. In addition, they behave as cytoplasmic relay molecules by regulating downstream signaling proteins, including several other protein kinases. These pathways allow enzymatic amplification of the signal and provide a way for different signals from other pathways to be integrated. However, the importance of the signaling proteins downstream of the MAPKs is still not fully understood. Now, three reports in this issue on pages 1358, 1362, and 1365, respectively (1-3), show that cell survival and cell cycle regulation by a MAPK signaling pathway (the p42/p44 ERK pathway) involves the pp90 ribosomal S6 kinases (Rsks) as crucial downstream effector molecules.

Rsks (also referred to as MAPKAP kinases-1) are a family of 85-to 90-kD proteins that are widely expressed in higher eukaryotes. In yeast, Rsk-related protein kinases have not been identified so far. Mammals have at least three Rsk isoforms—Rsk-1, Rsk-2, and Rsk-3—that are all specifically activated through phosphorylation by ERK MAPKs but not by other MAPK subfamilies. Mutations in human Rsk-2 are associated with Coffin-Lowry syndrome, an X-linked disorder characterized by mental retardation and skeletal abnormalities. Rsks are unusual protein kinases in that they contain two kinase domains in a single polypeptide (see the figure). The amino-terminal domain of Rsk is required for phosphorylation of substrates such as the transcription factors CREB and c-fos and the protein kinase Myt1. The carboxyl-terminal domain is able to phosphorylate the linker sequence between the two kinase domains and in this way is thought to regulate the activity of the amino terminus. Rsks also contain an α helix downstream of the carboxyl-terminal domain, which upon deletion or mutation results in a permanently activated protein kinase (4). The phosphorylation and activation of Rsks by the ERK subfamily of MAPKs is dependent on the presence of a MAPK docking site at the carboxyl terminus (see the figure)(5, 6). Although phosphorylation by MAPKs is essential, complete Rsk activation also requires phosphorylation of the amino-terminal domain by PDK1 (phosphoinositide-dependent kinase 1)(7, 8). Thus, Rsk activation integrates regulatory inputs from both the MAPK-and PDK1-dependent signaling pathways. Curiously, the results reported by Gross et al.(2) point to an additional inhibitory role for the amino-terminal 43 amino acids of Rsks, suggesting that there may be additional mechanisms of Rsk regulation.