IndraLab
Statements
"Together, these results suggest a mechanism in which 3' phosphoinositide lipid-dependent translocation of pkb to the plasma membrane promotes serine 473 phosphorylation, which is, in turn, necessary for pdk1-mediated phosphorylation of threonine 308 and, consequentially, full pkb activation."
rlimsp
"In the plasma membrane, Akt1 is phosphorylated at its two residues, Thr308 and Ser473. - Thr308 is phosphorylated by phosphoinositide-dependent kinase-1 (PDK1), and Ser473 by mTOR complex 2 (mTORC2). , There is also evidence showing Ser473 phosphorylation precedes and facilitates Thr308 phosphorylation by PDK1, and their phosphorylation leads to the activation of Akt1., On this basis, constitutively active forms of Akt1 (CA-Akt1) have been developed by directly targeting Akt1 to the plasma membrane, or by mimicking phosphorylation of the two sites."
sparser
"Two phosphorylation events are necessary for maximal activation of Akt, namely phosphorylation at Thr308 and Ser473 in Akt1 (Thr309/Ser474 in Akt2 and Thr305/Ser472 in Akt3) by phosphoinositide-dependent protein kinase 1 (PDK1) and the mechanistic target of rapamycin (mTOR) complex 2 (mTORC2), respectively [ xref , xref ]."
"Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. In this paper, we demonstrate that this is indeed the case, and report the purification and initial characterization of a 3 phosphoinositide-dependent protein kinase, pdk1, which activates pkb by phosphorylating it at thr308. Akt is directly phosphorylated and activated by pdk1. Akt/pkb activation requires the phosphorylation of thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (pdk1)."
rlimsp
"Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. RESULTS: The kinase domain of PDK1 interacts with a region of protein kinase C-related kinase-2 (PRK2), termed the PDK1-interacting fragment (PIF). PIF is situated carboxy-terminal to the kinase domain of PRK2, and contains a consensus motif for phosphorylation by PDK2 similar to that found in PKBalpha, except that the residue equivalent to Ser473 is aspartic acid. Mutation of any of the conserved residues in the PDK2 motif of PIF prevented interaction of PIF with PDK1. Remarkably, interaction of PDK1 with PIF, or with a synthetic peptide encompassing the PDK2 consensus sequence of PIF, converted PDK1 from an enzyme that could phosphorylate only Thr308 of PKBalpha to one that phosphorylates both Thr308 and Ser473 of PKBalpha in a manner dependent on phosphatidylinositol (3,4,5) trisphosphate (PtdIns(3,4,5)P3)."
rlimsp
"PKB is regulated by phosphorylation on Thr308 by 3-phosphoinositide-dependent protein kinase 1 (PDK1) and on Ser473 by an unidentified kinase. We have used chimeric molecules of PKB to define different steps in the activation mechanism. A chimera which allows inducible membrane translocation by lipid second messengers that activate in vivo protein kinase C and not PKB was created. Following membrane attachment, the PKB fusion protein was rapidly activated and phosphorylated at the two key regulatory sites, Ser473 and Thr308, in the absence of further cell stimulation."
sparser
"Another example of a scaffolding circRNA is circAMOTL1, which binds to pyruvate dehydrogenase kinase 1 (PDK1) and AKT serine/threonine kinase 1 (AKT1), leading to AKT1 phosphorylation at T308 by PDK1 and nuclear translocation, where it exerts antiapoptotic and differentiation functions xref ."
sparser
"This pathway is initiated by receptor tyrosine kinase (RTK) or G-protein coupled receptor activation, like CXCR4, thus inducing phosphorylation of PIP2 to PIP3 by PI3K, thereby recruiting AKT1 and phosphoinositide-dependent kinase (PDK1) to the plasma membrane, where AKT1 is phosphorylated by PDK1 at T308."
reach
"This pathway is initiated by receptor tyrosine kinase (RTK) or G-protein coupled receptor activation, like CXCR4, thus inducing phosphorylation of PIP2 to PIP3 by PI3K, thereby recruiting AKT1 and phosphoinositide-dependent kinase (PDK1) to the plasma membrane, where AKT1 is phosphorylated by PDK1 at T308."
rlimsp
"The Akts possess a PH domain and conserved residues (Thr308 and Ser473 in Akt1, the most commonly expressed isoform in normal cells) which are critical for Akt activation. Specifically, Akt translocated to the plasma membrane in response to products of PI3K, is activated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2 [4], [5]."
reach
"In general, receptor- or non-receptor tyrosine kinases, PI3K, the 3-phosphoinositide-dependent protein kinase 1 (PDK1) and mTOR complex 2 (mTORC2) can activate Akt by promoting the phosphorylation of Akt1, Akt2 and Akt3 at residues T308/S473, T309/S474 and T305/S472, respectively [83]."
rlimsp
"During growth factor–mediated activation of Akt1, the PH domain forms a new interaction with PIP3, causing it to move outward, away from the now more accessible kinase domain. This PH-out conformation is readily activated via phosphorylation at Thr308 by PDK1 and Ser473 by mTORC2."