Phospho-p70S6 Kinase (Thr421/Ser424)

The 70 kDa ribosomal protein S6 kinase (p70S6K) regulates cell growth by promoting protein synthesis and cell survival. The mammalian target of rapamycin (mTOR) is a key kinase acting downstream of the activation of the phosphoinositide 3-kinase (PI3K). P70S6K is a well-characterized target of mTOR, of which the signaling pathway is frequently activated in human cancers and has recently been recognized as an essential and attractive therapeutic target for cancer therapy. Selection of patients based on the detection of activated p70S6K or AKT and/or loss of phosphatase and tensin homolog (PTEN) expression might help predict tumor cells’ sensitivity to rapamycin analogs. Activation of mTOR results in the phosphorylation of p70S6K and the downstream phosphorylation of ribosomal protein S6, resulting in translational initiation and cell growth. Immunoreactivity of pS6 ribosomal protein Ser235/236 suggests a high incidence of mTOR/p70S6K signaling pathway activation. Inhibition of mTOR with rapamycin blocks Thr389 phosphorylation but not Thr421/Ser424 phosphorylation of S6K. Therefore, during protein kinase C activation, the c-Raf/MEK/extracellular signal-regulated kinase-1/2 (ERK1/2) pathway mediates both Thr421/Ser424 and Thr389 phosphorylation in an mTOR independent and dependent manner, respectively.