What does S6K1 do?
The mTORC1-S6K1 pathway regulates multiple cellular functions including cell cycle, apoptosis, glucose metabolism, protein synthesis and autophagy. This pathway has also been identified as one of the critical regulators of HSC and AML cells.
What phosphorylates S6?
S6 kinases (S6Ks) are mechanistic target of rapamycin substrates that participate in cell growth control. S6Ks phosphorylate ribosomal protein S6 (rpS6) and additional proteins involved in the translational machinery, although the functional roles of these modifications remain elusive.
What is P rpS6?
Ribosomal protein S6 (rpS6 or eS6) is a component of the 40S ribosomal subunit and is therefore involved in translation. Mouse model studies have shown that phosphorylation of eS6 is involved in the regulation of cell size, cell proliferation, and glucose homeostasis.
Is 4E BP activated by phosphorylation?
Phosphorylation of 4E-BP1 causes its release from eIF4E to allow cap-dependent translation to proceed. Recently, 4E-BP1 was shown to be phosphorylated by other kinases besides mTOR, and overexpression of 4E-BP1 was found in different human carcinomas.
Does mTOR inhibit 4EBP1?
p-4EBP1 Levels Are High in SHH-Group Medulloblastoma in Humans We found that inhibitory phosphorylation of 4EBP1 by mTORC1 is essential for HH signaling. Consistent with this, SMOM2- driven mouse medulloblastoma was dependent on mTORC1 and had high levels of p-4EBP1 (Figures 1A and 1E).
What does 4E-BP1 do?
4E-BP1 interdicts translation initiation by binding to the translation factor eIF4E, which is a limiting component of the multi-subunit complex that recruits 40S ribosomal subunits to the 5′-cap of mRNAs.
Does mTOR phosphorylate 4E BP?
FRAP/mTOR is demonstrated to phosphorylate 4E-BP1 in an eIF4E/4E-BP1 complex. Thr-37 and Thr-46 are phosphorylated to a high degree in serum-starved cells, in which most of the 4E-BP1 is complexed to eIF4E.
What phosphorylates 4ebp1?
ERK phosphorylates 4E-BP1 at Ser 65, and also blocks TSC2, leading to greater mTOR activity and increased phosphorylation of 4E-BP1. It is likely that ERK acts directly on 4E-BP1 and indirectly via TSC2/mTOR following ionizing radiation (IR) and stimulates protein synthesis via ATM-dependent ERK phosphorylation.
Does rapamycin increase general translation?
A cross-talk was suggested between the two pathways by rapamycin-induced translation of GCN4 mRNA. Here we show that rapamycin causes an increase in phosphorylated eIF2alpha to translationally derepress GCN4. This increment is not observed in the cells expressing mammalian non-GCN2 eIF2alpha kinases in place of GCN2.
Is rpS6 the only substrate of S6K?
For a long time, rpS6 is studied as the only substrate of S6K. However, there are more new other proteins shown to be substrates of S6K. There are more than 9 substrates have been discovered so far, but their activity and regulation are not all well described. Actually, there are some criteria to settle a protein as the substrate of S6K.
What is the structure of S6K1 and S6K2 protein?
Both of S6K1 and S6K2 protein are composed of some critical regulatory domains including an acidic N terminal region which contains the TOS (TOR signaling) motif, the kinase domain with T-loop and a basic C terminal region with an autoinhibitory pseudo-substrate domain. In addition, there is a linker region that contains the TM and HM sites.
Can serine be phosphorylated by S6K in vitro?
First of all, it is important to have the conformity of the phosphorylated serine’s sequence context with the consensus S6K recognition motif. Second, it can be phosphorylated by S6K in vitro. Third, there should be a correlation of the phosphorylation status in vivo with S6K activity.
What is the mechanism of action of S6K1 signaling?
S6K1 signaling impose a repressing effect on IRS-1 gene expression, which directly phosphorylates IRS-1 on several inhibitory serine residues. At the same time, mTOR phosphorylates IRS-1 (Ser636/Ser639). This phosphorylation of IRS-1 serine initiates IRS-1 degradation via the proteasome.