IndraLab

"A recent bioinformatics study performed KEGG analysis and gene set enrichment analysis (GSEA) via Gene Expression Profiling Interactive Analysis (GEPIA) based on The Cancer Genome Atlas (TCGA) datasets and demonstrated that ACTL6A significantly affects ribosomal pathways. xref Since S6 kinase (S6K1) is a key member of the pathway, that participates in translational control, and the S6 kinase (S6K1)-S6 signaling pathway is critical for regulating proliferation and survival in response to growth factors, we focused on S6K1 as a downstream target of ACTL6A. xref S6K1 always phosphorylates S6 protein at Ser235, Ser236, Ser240, Ser244, and Ser247. xref Aberrant upregulation of S6 phosphorylation and increased S6K activity are frequently present in various tumors including ESCC. xref Although phosphorylated-ribosomal protein S6 (p-S6) is considered to be a potential target in ESCC in vitro and S6 phosphorylation has prognostic significance in ESCC, the relationship between S6 and ACTL6A remains unclear. xref "

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"PRAS40 is required for mTORC1 signaling to p70S6 kinase, which, in turn, enables p70S6 kinase to phosphorylate S6 at Ser235/236."

"In fact, S6Ks phosphorylate rpS6 on S235 (structurally equivalent to S240 in Arabidopsis), S236, S240, and S244, while RSKs (absent in plants) phosphorylate only two residues (S235 and S236) ( xref )."

"The phosphorylation of rpS6 at S235 and S236 can be mediated by RSK and/or p70S6K."

"A knockin mouse carrying mutations at all phosphorylation sites in the primary s6k substrate, ribosomal protein s6 (rps6), has provided insight into the physiological role of this protein phosphorylation event. Of the many known substrates of s6k1, it is rps6 that has been shown to be directly involved, via its phosphorylation, in controlling cell size."

"The experiments described here have identified phosphorylation of ribosomal protein S6 at its S240 and S235 residues as specific readouts of mTOR hyperactivity vs. combined mTOR and MAPK hyperactivity, respectively. Early test tube studies using purified rat S6K1 and ribosomes concluded that S6K1 can phosphorylate both sites on S6 [47]. Subsequent studies in cells [48], [49] found that RSK is primarily responsible for S6(S235) phosphorylation and perusal of the data in these reports suggested to us that S235 phosphorylation is dependent upon or greatly enhanced by prior S240 phosphorylation by S6K1."

"After stimulation, S6K1 phosphorylates S6 on five serine residues (S235, S236, S240, S244, and S247) within the C-terminus [XREF_BIBR]."

"mTOR signaling activates p70S6 kinase which in turn phosphorylates Ser235, Ser236, Ser240 and Ser244 of S6."

"Ribosomal protein S6 is a component of a 40S ribosomal subunit which has been previously shown to be phosphorylated at Ser235/236 by S6K1, a downstream effector of mTOR (29)."

"S6K1 subsequently phosphorylates Ser235, Ser236, Ser240, and Ser244 of the S6 protein, promoting the activation of S6 and ultimately enhancing ribosome [ xref , xref ]."

"The phosphorylation of all five sites of S6 (Ser236, Ser235, Ser240, Ser244, and Ser247) could be carried out by S6K1."

"Ribosomal S6 kinase1 (S6K1), a downstream effector of mTORC1, phosphorylates ribosomal protein S6 at serine 235, 236, 240, 244 and 247 and the ratio of pS6 S235/236 / S6 was used as the functional marker of mTORC1 kinase activity 9."

"XREF_BIBR S6K1 always phosphorylates S6 protein at Ser235, Ser236, Ser240, Ser244, and Ser247."

"Similarly, p70 S6 kinase-mediated phosphorylation of ribosomal S6 at S235 and S240 was comparable between WT and Dapk −/− T cells ( xref )."

"Furthermore, inhibition of p70S6K with LY2584702 reduced RPS6 phosphorylation at S235:236 and S240:244 in the E420K and E198K variant cell lines (Figure 6D–F)."

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"AKT1S1 (PRAS40) contains a consensus phosphorylation motif and is a direct substrate for AKT, a mediator of PI3K signaling [26], while RPS6 is phosphorylated at Ser235/236 by p70S6 kinase."

"Interestingly, PRAS40 is required for mTORC 1 signaling to p70S6 kinase, which, in turn, enables p70S6 kinase to phosphorylate RPS6 at Ser235/236."