The human RPS6KA6 gene is located at Xq21, and contains 22 exons that span approximately 75 kb of genomic DNA and are located on cosmids E1, H22 and G9 in a telomeric to centromeric orientation (Yntema et al, 1999; Dümmler et al., 2005; Kantojärvi et al., 2011).

Human RPS6KA6 gene codes for the protein RSK4, a serine- threonine kinase with 745 amino acids, also a member of the 90 kDa ribosomal S6 kinase (RSK) family which includes other three members RSK1, RSK2 and RSK3 (Yntema et al., 1999; Dümmler et al., 2005; Anjum and Blenis, 2008; Serra et al., 2013).

RSK4 is a serine- threonine kinase and there are six phosphorylation sites in RSK4: Ser232, Thr368, Ser372, Ser389, Thr581, and Ser742. Upon activation of the cell surface receptors, ERK first bound to the ERK-docking motif in the carboxyl-terminal and phosphorylates Ser372 in the linker region and Thr581 in the CTKD. Phosphorylation of Thr581 activates CTK which autophosphorylates RSK4 at Ser389 in the linker region. Phosphorylation of Ser389 recruites and activiates PDK1 which phosphorylates Ser232 in NTKD. After dissociation of PDK1 from RSK, the Ser386 phosphorylated motif interacts with NTKD and activates the NTK in synergy with phosphor-Ser232. The phosphorylation of Ser372 increases the activity of NTK. Thr368 is phosphorylated by ERK and Ser742 can be phosphorylated by activated NTK, which leads to the association of RSK and ERK, serving as an inhibitory feedback mechanism to "shut off" the process (Dümmler et al., 2005). The CTKD activity of RSK1, RSK2 and RSK4 can be regulated by the irreversible inhibitor, pyrrolopyrimidine FMK (Z-VAD-FMK, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone) (Romeo et al., 2012).

RSK4 expression is low in both mouse and human embryonic and adult tissues compared with other three RSK family members. RSK4 mRNA was detected in the brain, cerebellum, heart, kidney and skeletal muscle, but not in other tissues such as lung, liver, pancreas and adipose. Specifically, RSK4 was found to be ubiquitously expressed at a low level through mouse development, and it is more highly expressed in specific phases of embryogenesis such as egg cylinder, gastrula and organ genesis (Kohn et al., 2003; Lleonart et al., 2006; Romeo et al., 2012).

RSK is predominantly located in cytosol, and contrary to other RSKs, its expression is relatively low and does not significantly accumulate in the nucleus after mitogenic stimulation (Dümmler et al., 2005; Romeo et al., 2012).

Recent studies showed RSK4 can be either oncogenic or tumor suppressive depending on many factors, and Cyclin D1 inhibited RSK4 expression and serum starvation enhanced the inhibition. RSK4 can induce cellular senescence which is mediated by p21. Also, inhibition of RSK4 causes bypass of cellular senescence induced by stress or oncogene, suggesting RSK4 inhibition may be an important factor in facilitating cell transformation. (López-Vicente et al., 2011). shRNA against RPS6KA6 bypassed p53-dependent G1 cell cycle arrest and suppressed mRNA expression of cyclin-dependent kinase inhibitor p21^cip1, suggesting RSK4 is needed for growth arrest induced by p53 (Berns et al., 2004). In addition, RSK4 is identified to be an inhibitor of fibroblast growth factor (FGF)-Ras-ERK signal transduction. RSK4 plays an inhibitory role during embryogenesis by suppressing receptor tyrosine kinase signaling (López-Vicente et al., 2009).

The RSK family members share 73-80% amino acids similarity to each other and are mostly different in their amino- and carboxyl-terminal sequences (Romeo et al., 2012). Difference from other RSK members whose activation needs the stimulation by growth factors, RSK4 can be constitutively activated under serum-starved condition without growth factor. The constitutive activation is due to constitutive phosphorylation of Ser232, Ser372 and Ser389 (Dümmler et al., 2005). PDK1 is required for mitogenic stimulation of RSK1-3, however, RSK4 does not appear to require PDK1 to maintain its high basal activity (Romeo et al., 2012). Unlike other three family members, RSK4 expression can disrupt mouse mesoderm formation induced by the FGF-Ras-ERK signaling pathway (Myers et al., 2004).