S6K2: The Neglected S6 Kinase Family Member

Abstract

S6 kinase 2 (S6K2) is a member of the AGC kinases super-family. Its closest homolog, S6K1, has been extensively studied along the years. However, due to the belief in the community that the high degree of identity between these two isoforms would translate in essentially identical biological functions, S6K2 has been largely neglected. Nevertheless, recent research has clearly highlighted that these two proteins significantly differ in their roles in vitro as well as in vivo. These findings are significant to our understanding of S6 kinase signaling and the development of therapeutic strategies for several diseases including cancer. Here, we will focus on S6K2 and review the protein–protein interactions and specific substrates that determine the selective functions of this kinase.

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

“…The two S6K isoforms, S6K1 and S6K2, were originally thought to be redundant proteins due to their high homology. However, recent studies suggest distinct roles for each isoform (reviewed in [5]). Indeed, S6K1 participates in insulinmediated cell growth but-like mTORC1-also operates negative feedback loops at various levels of regulation.…”

S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts

“…In addition, RPS6KB1 is a target gene for ER transcription (Maruani et al 2012). S6K2 has recently been brought to light as a potentially important oncoprotein, with fewer essential roles in normal tissue than S6K1, making it an interesting treatment target (Pardo & Seckl 2013).…”

Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer

“…A recent review also highlights these indications [118]. In the light of this, it may be conceivable that isoform-specific targeting could be useful, allowing further tumour-specific therapies.…”

“…A structural comparison of the S6K1 and S6K2 kinase domains revealed significant differences that could be of importance for differences in regulation and function of the two kinases and also useful for future development of isoform-specific inhibitors. At the global tissue level, the expressions of S6K1 and S6K2 have been shown inversely correlated [118]. S6K1 are ubiquitously expressed, whereas the levels of S6K2 vary between tissue and the protein is mainly found in the central nervous system, lungs and gastrointestinal tracts.…”