THE enzymes p70(s6k) and p85(s6k) two isoforms of the same kinase(1,2) and are important in mitogenesis(2-4). Both isoforms are activated by a complex phosphorylation event(5) and lie on a common signalling pathway(4), distinct from that of the p42(mapk)/p44(mapk) kinases(6). Activation of p42(mapk)/p44(mapk) is triggered by sequential activation of the GDP-GTP exchange factor Sos, the GTP-binding protein p21(ras), and protein kinases p74(raf) and p47(mek) (refs 7-10). As p21(ras) transformed cells have increased S6 phosphorylation(11), we tested whether the p70(s6k)/p85(s6k) signalling pathway bifurcates between p21(ras) and p42(mapk)/p44(mapk). We found that mutants of p74(raf) and p21(ras) blocked activation of epitope-tagged p44(mapk) but not epitope-tagged p70(s6k). Moreover, in cells expressing human platelet-derived growth factor receptors lacking the kinase-insert domain, the growth factor activates p21(ras) but not p70(s6k)/p85(s6k). The critical autophosphorylation site for p70(s6k)/p85(s6k) activation within this domain is a tyrosine at residue 751. Our results show that the p70(s6k)/p85(s6k) signalling pathway is independent of p21(ras), that it bifurcates from the p21(ras) pathway at the receptor, and that it is initiated by autophosphorylation at a specific site.