S6 PHOSPHORYLATION AND THE P70(S6K)/P85(S6K)

Activation of cell growth leads to the multiple phosphorylation of 40S ribosomal protein S6. The kinase responsible for controling this event is termed p70(s6k)/ p85(s6k). Both isoforms of the kinase are derived from a common gene activated by a complex set of phosphorylation events; each resides in a unique cellular compartment: the p70(s6k) in the cytoplasm and the p85(s6k) in the nucleus. Although p70(s6k)/p85(s6k) represent the first mitogen-activated serine/threonine kinase described, the signaling pathway leading to activation of both isoforms remains obscure. Recent studies have shown that this pathway is distinct from that of p21(ras) and the p42(mapk)/p44(mapk), and that bifurcation of these pathways takes place at the level of the receptor. Experiments with point mutants of the PDGF receptor and inhibitors of phosphatidyl-inositol-3-OH kinase have implicated the latter molecule in this signaling event, but more recent findings suggest an alternative route may be employed. The p70(s6k) signaling pathway can also be ablated by the immunosuppressant rapamycin, which blocks p70(s6k) activation and S6 phosphorylation without affecting the other kinases whose activation is triggered by mitogen treatment. In parallel, rapamycin suppresses the translation of a family of mRNAs that contain a polypyrimidine tract at their 5' transcriptional start site. The implication is that this event is mediated by the phosphorylated form of S6 that may either (1) directly interact with the polypyrimidine tract or (2) alter the affinity of the 40S ribosome mRNA binding site for polypyrimidine tract mRNAs, or (3) recognize proteins that directly bind to the polypyrimidine tract.