p70s6K Signaling
p70s6K and eIF4 play important, complementary roles in promoting mRNA translation, making them key regulators of protein synthesis and cellular growth. Both are activated by mTOR in response to nutrient and energy status and growth factor signals. Both are also frequently activated in a variety of cancers, making p70s6K in particular an attractive alternative therapeutic target to mTOR.
mRNA translation regulation pathways
p70s6K signaling
p70s6K is a serine-threonine kinase that, when activated, phosphorylates ribosomal protein S6, which is a component of the 40S ribosomal subunit. Ribosomal protein S6 phosphorylation results in enhanced translation of a specific subset of mRNAs containing polypyrimidine tracts at their 5’ end. Many of these mRNAs encode ribosomal proteins and protein synthesis elongation factors, making p70s6K a key factor in protein synthesis and cellular growth.
Activation of p70s6K involves a complex, ordered series of conformational changes and phosphorylation at multiple sites (1). Although p70s6K maximal activation has been shown to be influenced by additional factors, mTOR, which is itself activated by PI3K/PDK/AKT signaling, is the key regulator of p70s6K phosphorylation and activation.
eIF4 signaling
Of note, eIF4 is also activated by mTOR (2). eIF4 (Eukaryotic Initiation Factor 4) is a trimeric complex composed of EIF4A, EIF4E and EIF4G that also plays a critical role in translation initiation. When released from 4E-BP1 (4E binding protein 1), EIF4E stimulates translation by binding the 5’ cap of mRNAs and helping to recruit ribosomes to the mRNAs. mTOR exerts its positive effect on eIF4 via phosphorylation of 4E-BP1, causing release of EIF4E.
p70s8K and eIF4 are linked by their complementary roles in translation initiation and shared regulation by mTOR. Both, like mTOR, are frequently found in an unregulated, activated state in a variety of cancers where they drive increased protein synthesis and abnormal cellular growth. mTOR is the target of the anti-cancer drug rapamycin, but both p70s8K and eIF4 are of interest as potential additional targets.
References
- Artemenko M, Zhong SSW, To SKY, Wong AST. p70 S6 kinase as a therapeutic target in cancers: More than just an mTOR effector. Cancer Lett. 2022;535:215593
- Maracci C, Motta S, Romagnoli A, Costantino M, Perego P, Daniele Di Marino D. The mTOR/4E-BP1/eIF4E signalling pathway as a source of cancer drug targets. Curr Med Chem. 2022;29(20):3501-3529