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 even t is termed p70(s6k)/ p85(s6k). Both isoforms of the kinase are derive d from a common gene activated by a complex set of phosphorylation eve nts; each resides in a unique cellular compartment: the p70(s6k) in th e cytoplasm and the p85(s6k) in the nucleus. Although p70(s6k)/p85(s6k ) represent the first mitogen-activated serine/threonine kinase descri bed, the signaling pathway leading to activation of both isoforms rema ins obscure. Recent studies have shown that this pathway is distinct f rom that of p21(ras) and the p42(mapk)/p44(mapk), and that bifurcation of these pathways takes place at the level of the receptor. Experimen ts with point mutants of the PDGF receptor and inhibitors of phosphati dyl-inositol-3-OH kinase have implicated the latter molecule in this s ignaling 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 activati on is triggered by mitogen treatment. In parallel, rapamycin suppresse s the translation of a family of mRNAs that contain a polypyrimidine t ract at their 5' transcriptional start site. The implication is that t his 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 trac t mRNAs, or (3) recognize proteins that directly bind to the polypyrim idine tract.