The RNA-binding protein AUF1 facilitates Akt phosphorylation at the membrane

Abstract

Mammalian target of rapamycin (mTOR), which is part of mTOR complex 1 (mTORC1) and mTORC2, controls cellular metabolism in response to levels of nutrients and other growth signals. A hallmark of mTORC2 activation is the phosphorylation of Akt, which becomes upregulated in cancer. How mTORC2 modulates Akt phosphorylation remains poorly understood. Here, we found that the RNA-binding protein, AUF1 (ARE/poly(U)-binding/degradation factor 1), modulates mTORC2/Akt signaling. We determined that AUF1 is required for phosphorylation of Akt at Thr308, Thr450, and Ser473 and that AUF1 also mediates phosphorylation of the mTORC2-modulated metabolic enzyme glutamine fructose-6-phosphate amidotransferase 1 at Ser243. In addition, AUF1 immunoprecipitation followed by quantitative RT–PCR revealed that the mRNAs of Akt, glutamine fructose-6-phosphate amidotransferase 1, and the mTORC2 component SIN1 associate with AUF1. Furthermore, expression of the p40 and p45, but not the p37 or p42, isoforms of AUF1 specifically mediate Akt phosphorylation. In the absence of AUF1, subcellular fractionation indicated that Akt fails to localize to the membrane. However, ectopic expression of a membrane-targeted allele of Akt is sufficient to allow Akt-Ser473 phosphorylation despite AUF1 depletion. Finally, conditions that enhance mTORC2 signaling, such as acute glutamine withdrawal, augment AUF1 phosphorylation, whereas mTOR inhibition abolishes AUF1 phosphorylation. Our findings unravel a role for AUF1 in promoting membrane localization of Akt to facilitate its phosphorylation on this cellular compartment. Targeting AUF1 could have therapeutic benefit for cancers with upregulated mTORC2/Akt signaling. Mammalian target of rapamycin (mTOR), which is part of mTOR complex 1 (mTORC1) and mTORC2, controls cellular metabolism in response to levels of nutrients and other growth signals. A hallmark of mTORC2 activation is the phosphorylation of Akt, which becomes upregulated in cancer. How mTORC2 modulates Akt phosphorylation remains poorly understood. Here, we found that the RNA-binding protein, AUF1 (ARE/poly(U)-binding/degradation factor 1), modulates mTORC2/Akt signaling. We determined that AUF1 is required for phosphorylation of Akt at Thr308, Thr450, and Ser473 and that AUF1 also mediates phosphorylation of the mTORC2-modulated metabolic enzyme glutamine fructose-6-phosphate amidotransferase 1 at Ser243. In addition, AUF1 immunoprecipitation followed by quantitative RT–PCR revealed that the mRNAs of Akt, glutamine fructose-6-phosphate amidotransferase 1, and the mTORC2 component SIN1 associate with AUF1. Furthermore, expression of the p40 and p45, but not the p37 or p42, isoforms of AUF1 specifically mediate Akt phosphorylation. In the absence of AUF1, subcellular fractionation indicated that Akt fails to localize to the membrane. However, ectopic expression of a membrane-targeted allele of Akt is sufficient to allow Akt-Ser473 phosphorylation despite AUF1 depletion. Finally, conditions that enhance mTORC2 signaling, such as acute glutamine withdrawal, augment AUF1 phosphorylation, whereas mTOR inhibition abolishes AUF1 phosphorylation. Our findings unravel a role for AUF1 in promoting membrane localization of Akt to facilitate its phosphorylation on this cellular compartment. Targeting AUF1 could have therapeutic benefit for cancers with upregulated mTORC2/Akt signaling. Cells respond to the availability of nutrients by controlling gene expression at the level of both transcription and translation. Mammalian target of rapamycin (mTOR) plays a central role in sensing the nutritional status of the cell and triggers a cascade of intracellular signaling that ultimately promotes anabolic metabolism, growth, and proliferation (1Szwed A. Kim E. Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2.Physiol. Rev. 2021; 101: 1371-1426Crossref PubMed Scopus (215) Google Scholar, 2Shimobayashi M. Hall M.N. Making new contacts: the mTOR network in metabolism and signalling crosstalk.Nat. Rev. Mol. Cell Biol. 2014; 15: 155-162Crossref PubMed Scopus (851) Google Scholar, 3Saxton R.A. Sabatini D.M. mTOR signaling in growth, metabolism, and disease.Cell. 2017; 169: 361-371Abstract Full Text Full Text PDF PubMed Scopus (1261) Google Scholar). Deregulation of mTOR signaling occurs in many diseases, including cancer, diabetes, autoimmunity, and neurological disorders. Dampening mTOR signals is a promising strategy for the treatment of these diseases and to improve health span (4Magaway C. Kim E. Jacinto E. Targeting mTOR and metabolism in cancer: lessons and innovations.Cells. 2019; 8: 1-51Crossref Scopus (134) Google Scholar, 5Partridge L. Fuentealba M. Kennedy B.K. The quest to slow ageing through drug discovery.Nat. Rev. Drug Discov. 2020; 19: 513-532Crossref PubMed Scopus (223) Google Scholar). mTOR forms two distinct protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Many studies have revealed how mTORC1, which is sensitive to rapamycin, is regulated by nutrients and how intracellular signaling molecules mediate its functions. In contrast, how mTORC2 is regulated and the identity of its downstream effectors remain poorly understood (6Fu W. Hall M.N. Regulation of mTORC2 signaling.Genes (Basel). 2020; 11: 1045Crossref Scopus (111) Google Scholar). One of the hallmarks of increased mTORC2 activation is the allosteric phosphorylation of Akt at the hydrophobic motif site, Ser473 (7Jacinto E. Facchinetti V. Liu D. Soto N. Wei S. Jung S.Y. et al.SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity.Cell. 2006; 127: 125-137Abstract Full Text Full Text PDF PubMed Scopus (1181) Google Scholar, 8Sarbassov D.D. Guertin D.A. Ali S.M. Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.Science. 2005; 307: 1098-1101Crossref PubMed Scopus (5477) Google Scholar, 9Hresko R.C. Mueckler M. mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes.J. Biol. Chem. 2005; 280: 40406-40416Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar). Upon growth factor signaling, PI3K becomes activated leading to increased phosphatidylinositol 3,4,5-trisphosphate (PIP3) levels in the membrane. Enhanced PIP3 levels attract signaling molecules with the pleckstrin homology (PH) domain, such as Akt, to the membrane where it becomes phosphorylated at the activation loop site, Thr308, by PDK1 and at Ser473 via an mTORC2-dependent mechanism (8Sarbassov D.D. Guertin D.A. Ali S.M. Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.Science. 2005; 307: 1098-1101Crossref PubMed Scopus (5477) Google Scholar, 9Hresko R.C. Mueckler M. mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes.J. Biol. Chem. 2005; 280: 40406-40416Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar, 10Alessi D.R. Andjelkovic M. Caudwell B. Cron P. Morrice N. Cohen P. et al.Mechanism of activation of protein kinase B by insulin and IGF-1.EMBO J. 1996; 15: 6541-6551Crossref PubMed Scopus (2576) Google Scholar, 11Manning B.D. Toker A. AKT/PKB signaling: navigating the network.Cell. 2017; 169: 381-405Abstract Full Text Full Text PDF PubMed Scopus (2207) Google Scholar). Both PDK1 and mTORC2 have been found to localize on the membrane. PDK1 and the mTORC2 components SIN1 and possibly rictor each harbor a PH domain that could deliver them to the membrane to promote Akt activation (12Bayascas J.R. Wullschleger S. Sakamoto K. Garcia-Martinez J.M. Clacher C. Komander D. et al.Mutation of the PDK1 PH domain protein kinase leading to and insulin Cell Biol. PubMed Scopus Google Scholar, M. N. A. et and pleckstrin homology and 19: PubMed Scopus Google Scholar, P. N. B. the domain of the target of rapamycin complex component rictor Biol. PubMed Scopus Google Scholar). In to phosphorylation at mTORC2 also mediates Akt phosphorylation at the site, V. W. Wei Soto N. A. C. et target of rapamycin complex 2 controls and of Akt and protein kinase J. PubMed Scopus Google Scholar, K. of in and Akt motif phosphorylation, and J. PubMed Scopus Google Scholar). the phosphorylation of this is PI3K and occurs Kim Facchinetti V. M. et associate with to promote phosphorylation and of Akt J. PubMed Scopus Google Scholar). phosphorylation is sensitive to and acute V. D. et of the target of rapamycin (mTOR) complex 2 integrity is by an Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We and have that mTORC2 is activated of nutrients such as or glutamine Kim S. M. et to glutamine levels to the enzyme Full Text Full Text PDF PubMed Scopus Google Scholar, D. B. C. D. et mTORC2 to promote cell acute 2019; PubMed Scopus Google Scholar). mTORC2 to the levels of intracellular glutamine or glutamine Kim S. M. et to glutamine levels to the enzyme Full Text Full Text PDF PubMed Scopus Google Scholar). activation is to through the via of the enzyme of the glutamine fructose-6-phosphate amidotransferase 1 findings that mTORC2 not to the of growth signals but also to in to metabolic that the expression levels of mTORC2 components could its and occurs in K. Liu B. et a of with benefit treatment with Discov. PubMed Scopus Google Scholar, Liu expression in cell and its 2017; PubMed Scopus Google Scholar, J. A. J. A. et is in and promotes growth and cell via of PubMed Scopus Google Scholar, M. B. V. C. et and therapeutic of PubMed Scopus Google Scholar, L. J. J. et of protein in is with and 2017; Google Scholar, D. M. The role of in and drug 2020; PubMed Scopus Google Scholar, J. C. et promotes proliferation and of by and signaling 2020; Scopus Google Scholar, J. B. et 1 promotes in via of SIN1 and mTOR complex 2 2020; PubMed Scopus Google Scholar). the central role of mTORC2 in metabolism and cell a of the of mTORC2 regulation at the level of could on therapeutic in cancer. and immunoprecipitation the mRNAs mTORC2 components and the enzyme the of the RNA-binding protein AUF1 (ARE/poly(U)-binding/degradation factor also as S. S. K. Kim J. et AUF1 on target and 2014; PubMed Scopus Google Scholar). AUF1 been to the regulation of and W. K. D. et and of an RNA-binding protein, Cell Biol. PubMed Scopus Google Scholar, AUF1 to with Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, AUF1 Regulation of and Rev. 2017; PubMed Scopus Google Scholar). or but it remains how AUF1 distinct functions on A RNA-binding factor regulates in Cell Biol. 11: PubMed Scopus Google Scholar, N. role for isoforms in the regulation of Cell Biol. PubMed Scopus Google Scholar, B. C. of mRNAs by the p37 AUF1 protein Cell Biol. PubMed Scopus Google Scholar, J. et of RNA-binding protein 1 RNA-binding protein and the of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). for but studies that it in mRNAs and S. S. K. Kim J. et AUF1 on target and 2014; PubMed Scopus Google Scholar). AUF1 of isoforms that by of a and of the AUF1 protein PubMed Scopus Google Scholar). The isoforms with J. et of RNA-binding protein 1 RNA-binding protein and the of Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). on the role of regulation of mTORC2 components in mTORC2 B. A. et a loop expression and growth in PubMed Scopus Google Scholar, J. C. et to in 2017; PubMed Scopus Google Scholar, B. K. J. S. L. et via the mTOR component in 2017; 8: PubMed Scopus Google we how AUF1 in mTORC2 signaling and We found that AUF1 is required for the phosphorylation of Akt at the regulated by PDK1 and is the role of AUF1 in and of its We that AUF1 mediates the membrane localization of Akt where it is phosphorylated in response to growth signals. We also found that AUF1 is by signals that enhance mTORC2 Our findings a role for AUF1 in mTORC2 signaling. In a to that regulated by AUF1, components of the mTOR including mTOR and rictor by S. S. K. Kim J. et AUF1 on target and 2014; PubMed Scopus Google Scholar). We that AUF1 could mTOR signaling. the cell we AUF1 by of an expression and of both mTORC1 and mTORC2 signaling. phosphorylation of the mTORC2 target in Akt, Ser473 and Thr450, in but not in The phosphorylation of the activation loop in Akt, Thr308, which is by PDK1 also AUF1 We have that the metabolic enzyme of the by also in the S. S. K. Kim J. et AUF1 on target and 2014; PubMed Scopus Google Scholar). We its phosphorylation and found that it also AUF1 In contrast, phosphorylation of the mTORC1 target not with a mTORC2 signaling, a in SIN1 but not rictor expression in We also AUF1 in by with the expression or and found that the phosphorylation of Akt in but not in or and that the of on Akt phosphorylation not of an of the or an of phosphorylation also AUF1 in In contrast, the phosphorylation of the mTORC1 and the protein not the expression of and mTOR not AUF1 expression Furthermore, mTORC2 integrity not in as both mTOR and rictor with SIN1 of AUF1 expression levels the in Akt phosphorylation AUF1 in is of a on Akt, We AUF1 to Akt immunoprecipitation we AUF1 and by quantitative RT–PCR with Akt in the AUF1 that AUF1 forms an complex with Akt to AUF1, whereas not B. of AUF1 and to controls its Mol. Biol. PubMed Scopus Google Scholar). SIN1 expression AUF1 in but not we also AUF1 with SIN1 with the in expression of SIN1 in a but in of SIN1 with AUF1 in but not in Finally, phosphorylation also of AUF1, we its with AUF1. with the S. S. K. Kim J. et AUF1 on target and 2014; PubMed Scopus Google we that AUF1 to findings that AUF1 with mRNAs of Akt and other that to mTORC2 signaling. Akt phosphorylation occurs at the we AUF1 is in Akt in this compartment. cellular we found that whereas Akt to the in the it in this and in the in Akt Thr450, and in the in the The Akt that at the in In contrast, PDK1 localization in the and not in the absence of AUF1 2 and and findings that AUF1 the localization of Akt at the subcellular that in the Furthermore, AUF1 is required for Akt phosphorylation at these the findings that AUF1 is for Akt phosphorylation at the we AUF1 is required for Akt phosphorylation Akt is at the membrane. we the which Akt to the membrane V. W. Wei Soto N. A. C. et target of rapamycin complex 2 controls and of Akt and protein kinase J. PubMed Scopus Google or AUF1 expression the phosphorylation of at Ser473 to whereas the Akt phosphorylation of with a V. W. Wei Soto N. A. C. et target of rapamycin complex 2 controls and of Akt and protein kinase J. PubMed Scopus Google phosphorylation of that the kinase of Akt is required for Ser473 phosphorylation A. Akt/protein kinase B is regulated by at the Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). these findings that AUF1 mediates the membrane localization of Akt where it becomes phosphorylated at AUF1 of isoforms that by of a isoforms the motif and followed by a glutamine domain p40 and isoforms have an whereas and isoforms harbor an AUF1 is phosphorylated the domain at and J. K. S. B. et of regulates to A and in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Regulation of by phosphorylation and the PubMed Scopus Google Scholar). domain is in p40 and but not p37 and of these is to of a on AUF1 that could J. K. S. B. et of regulates to A and in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We which of these AUF1 isoforms required for Akt phosphorylation. in which AUF1 expression by of the expression we expression of each AUF1 in by a the that AUF1 to by in of S. S. AUF1 regulation of expression in PubMed Scopus Google Scholar). of and but not or phosphorylation of Akt in that the that the in AUF1 is required to mediate Akt phosphorylation and of the in which both and to Akt phosphorylation contrast, the of to Akt phosphorylation to of cell expression of each AUF1 The expression of and not by expression of of the AUF1 that the of these isoforms on Akt phosphorylation is not via of expression of each of these Akt signaling p40 and specifically Akt phosphorylation. we found that phosphorylated p40 is for Akt phosphorylation, we how AUF1 phosphorylation could by signals that enhance mTORC2 signaling. we how which mTORC2/Akt signaling, could AUF1 phosphorylation. increased Akt-Ser473 phosphorylation to and with a in AUF1 phosphorylation these We and have also that Akt phosphorylation Kim S. M. et to glutamine levels to the enzyme Full Text Full Text PDF PubMed Scopus Google Scholar, D. B. C. D. et mTORC2 to promote cell acute 2019; PubMed Scopus Google Scholar). of in Akt phosphorylation as as AUF1 phosphorylation of the increased AUF1 phosphorylation at to Akt phosphorylation. acute glutamine to in Akt Ser473 phosphorylation and this with increased AUF1 phosphorylation to glutamine Akt phosphorylation as we Kim S. M. et to glutamine levels to the enzyme Full Text Full Text PDF PubMed Scopus Google and AUF1 phosphorylation these Akt phosphorylation is by mTORC2 we AUF1 phosphorylation is also sensitive to this We which mTOR mTORC1 and and its on AUF1 phosphorylation and glutamine the in AUF1 phosphorylation and glutamine it Akt-Ser473 phosphorylation. findings that AUF1 phosphorylation is by signals that enhance mTORC2 signaling. Akt phosphorylation is a hallmark of B.D. Toker A. AKT/PKB signaling: navigating the network.Cell. 2017; 169: 381-405Abstract Full Text Full Text PDF PubMed Scopus (2207) Google Scholar). We AUF1 could upregulated in with increased Akt phosphorylation. We The to AUF1 expression in B. B. et a for gene expression and 2017; 19: PubMed Scopus Google Scholar). of cancers with increased AUF1 gene expression However, these and a that is to B and We the expression of AUF1 in a cell Upon with Akt phosphorylation with AUF1 expression with the of in AUF1 expression in these findings that AUF1 expression is sensitive to mTOR inhibition in mTORC2 is activated by growth signaling and (1Szwed A. Kim E. Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2.Physiol. Rev. 2021; 101: 1371-1426Crossref PubMed Scopus (215) Google Scholar, W. Hall M.N. Regulation of mTORC2 signaling.Genes (Basel). 2020; 11: 1045Crossref Scopus (111) Google Scholar). is required for phosphorylation, and of How mTORC2 signaling is and how mTORC2 mediates Akt phosphorylation remain poorly understood. In the we found that AUF1, an in and is for Akt phosphorylation in the membrane. is also required for the phosphorylation of a metabolic enzyme that we have to by mTORC2 Kim S. M. et to glutamine levels to the enzyme Full Text Full Text PDF PubMed Scopus Google Scholar, Liu S. C. Kim et modulates the and of phosphorylation to through the Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In AUF1 is phosphorylated conditions that enhance mTORC2 Our findings that in to a role for AUF1 in and it modulates mTORC2 signaling. mTORC2 is for the phosphorylation of Akt at and Ser473 (7Jacinto E. Facchinetti V. Liu D. Soto N. Wei S. Jung S.Y. et al.SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity.Cell. 2006; 127: 125-137Abstract Full Text Full Text PDF PubMed Scopus (1181) Google Scholar, 8Sarbassov D.D. Guertin D.A. Ali S.M. Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.Science. 2005; 307: 1098-1101Crossref PubMed Scopus (5477) Google Scholar, V. W. Wei Soto N. A. C. et target of rapamycin complex 2 controls and of Akt and protein kinase J. PubMed Scopus Google Scholar, K. of in and Akt motif phosphorylation, and J. PubMed Scopus Google Scholar, J.M. A. W. et controls the of and Akt by a 2021; PubMed Scopus Google Scholar). Akt phosphorylation at the activation loop site, Thr308, by PDK1 Akt, the phosphorylation at and Ser473 Akt and Here, we have that AUF1 is required for phosphorylation of these in Akt studies in have also that of AUF1 Akt phosphorylation J. Liu et of AUF1 in a and promotes by and 2020; PubMed Scopus Google Scholar). we that AUF1 promotes Akt phosphorylation by its membrane The of AUF1 Akt the Akt phosphorylation the phosphorylation of Akt at Ser473 and occurs PI3K activation PDK1 and mTORC2 both localize at the findings that AUF1 phosphorylation of Akt in the membrane compartment. in to the Akt PH domain, which to PIP3 that in M. Andjelkovic M. E. J.R. of and to the pleckstrin homology domain of kinase B and on kinase Biol. Chem. Full Text Full Text PDF PubMed Scopus Google AUF1 is also for this membrane localization to allow Akt phosphorylation. with the role of AUF1 in phosphorylation of Akt, AUF1 is also in the that Akt-Ser473 and phosphorylation, the phosphorylation of is not on PI3K but on mTORC2 V. W. Wei Soto N. A. C. et target of rapamycin complex 2 controls and of Akt and protein kinase J. PubMed Scopus Google Scholar, K. of in and Akt motif phosphorylation, and J. PubMed Scopus Google Scholar). phosphorylation occurs as the Akt the Kim Facchinetti V. M. et associate with to promote phosphorylation and of Akt J. PubMed Scopus Google Scholar). both mTORC2 and AUF1 associate with Kim Facchinetti V. M. et associate with to promote phosphorylation and of Akt J. PubMed Scopus Google Scholar, J. K. S. B. et of regulates to A and in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, V. D. W. Hall M.N. of mTORC2 by with the Full Text Full Text PDF PubMed Scopus Google Scholar, A. et of the protein AUF1 by activation of the Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google AUF1 promote phosphorylation of the Akt as part of the studies to how AUF1 could promote Akt phosphorylation via localization to membrane AUF1 is an with and functions AUF1 Regulation of and Rev. 2017; PubMed Scopus Google Scholar). on it or is also in other functions such as and Our studies that it to mRNAs of that in mTORC2 signaling. AUF1 been to Akt signals J. Liu et of AUF1 in a and promotes by and 2020; PubMed Scopus Google but studies for the that AUF1 to Akt The to Akt that it have a role in Akt and phosphorylation by possibly its to a membrane compartment. However, AUF1 also to mTOR and rictor as and to SIN1 as we B and it remains to how AUF1 could have a role in mTORC2 signaling in AUF1 to and controls its by for a with the B. of AUF1 and to controls its Mol. Biol. PubMed Scopus Google Scholar). mTORC2, to nutrients and controls and glutamine metabolism (1Szwed A. Kim E. Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2.Physiol. Rev. 2021; 101: 1371-1426Crossref PubMed Scopus (215) Google Scholar, to glutamine metabolism to Rev. PubMed Scopus Google Scholar). AUF1 could and regulation of remains to AUF1 modulates mTORC2 signaling via also remains to In this AUF1 been to localize at of of its L. A. A. M. C. L. et of the protein by and 2019; PubMed Scopus Google Scholar). the and of AUF1 with mTORC2 signaling components We also that AUF1 phosphorylation with mTORC2 signaling. signals that enhance mTORC2 signaling such as and glutamine AUF1 phosphorylation. AUF1 isoforms that by of the these p40 and which an to and the protein of this the and phosphorylation of AUF1 is by and is to regulation of AUF1 J. K. S. B. et of regulates to A and in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M. kinase A whereas the of the domain of in a J. PubMed Google Scholar, Wei Phosphorylation of protein 1 to of via with RNA-binding protein 1 and A protein 2017; PubMed Scopus Google Scholar). AUF1 phosphorylation is by signals that mTORC2 signaling, this that could signals mTORC2 to AUF1. How could mediate mTORC2 signals is poorly understood and remains to in V. K. M. M. S. V. et via and in Mol. 8: PubMed Scopus Google Scholar, of mTORC2 activation by the of in of a signaling Cell Google Scholar, M. P. kinase A regulates the and in response to the in Cell 2017; PubMed Scopus Google Scholar, A. M. protein via regulation of the protein kinase A and regulation of the protein kinase Biol. Chem. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). Phosphorylation of is by kinase and occurs is phosphorylated M. kinase A whereas the of the domain of in a J. PubMed Google Scholar). phosphorylation is to the of AUF1. this as mTORC2 signals In of this we found that AUF1 phosphorylation is sensitive to levels and mTOR AUF1 Akt phosphorylation and is a substrate of The phosphorylation at to promote cell and proliferation B.D. Toker A. AKT/PKB signaling: navigating the network.Cell. 2017; 169: 381-405Abstract Full Text Full Text PDF PubMed Scopus (2207) Google Scholar). it is that increased Akt activation could AUF1 phosphorylation at and by of mTORC2/Akt signaling is found in The increased phosphorylation of Akt is as a hallmark of increased proliferation in B.D. Toker A. AKT/PKB signaling: navigating the network.Cell. 2017; 169: 381-405Abstract Full Text Full Text PDF PubMed Scopus (2207) Google Scholar). mTOR and Akt to cancers and other (4Magaway C. Kim E. Jacinto E. Targeting mTOR and metabolism in cancer: lessons and innovations.Cells. 2019; 8: 1-51Crossref Scopus (134) Google Scholar, L. S. et new in the 2021; PubMed Scopus Google Scholar). AUF1 is in J. Liu et of AUF1 in a and promotes by and 2020; PubMed Scopus Google Scholar, M. A. J. A. et is with and its in PubMed Scopus Google Scholar, B. L. C. K. et role of AUF1 in PubMed Scopus Google Scholar, expression and localization of the protein and in PubMed Scopus Google Scholar, W. J. J. et of AUF1 is in the proliferation of cell through J. PubMed Scopus Google A and increased expression in and is with or J. Liu et of AUF1 in a and promotes by and 2020; PubMed Scopus Google Scholar). We have that inhibition of mTOR in the cell AUF1 expression and Akt phosphorylation Our findings that AUF1 could as a target for mTORC2/Akt signaling. studies to how AUF1 specifically Akt phosphorylation for of and metabolic disorders. AUF1 K. et modulates AUF1 and Cell Biol. PubMed Scopus Google and Liu S. C. Kim et modulates the and of phosphorylation to through the Biol. Chem. Full Text Full Text PDF PubMed Scopus Google SIN1 and other Cell with the Akt rictor mTOR PDK1 and The or AUF1 isoforms and AUF1 isoforms to as S. S. AUF1 regulation of expression in PubMed Scopus Google Scholar). and to and and to J. and protein promote of factor Cell Biol. PubMed Scopus Google Scholar). for AUF1 and Akt or Akt V. W. Wei Soto N. A. C. et target of rapamycin complex 2 controls and of Akt and protein kinase J. PubMed Scopus Google Scholar). with or and for as S. S. AUF1 regulation of expression in PubMed Scopus Google Scholar). of as J. and protein promote of factor Cell Biol. PubMed Scopus Google Scholar). of or and in in a to in or as to 2 of that with in followed by cell and with and cell and or AUF1 as J. A. et via allosteric of a 2020; 11: PubMed Scopus Google Scholar). and by the Akt SIN1 rictor mTOR and on with 2 and as Liu S. C. Kim et modulates the and of phosphorylation to through the Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with SIN1 and or at to in 2 glutamine and in with for to the in and in or glutamine as Kim S. M. et to glutamine levels to the enzyme Full Text Full Text PDF PubMed Scopus Google Scholar). The also to as or 2 Cells with and and determined by and to of to membrane with in with in with the in by and Cells in and at is as the The which of through a and at for at The in and at for 1 at The in and with and AUF1 expression the as B. B. et a for gene expression and 2017; 19: PubMed Scopus Google Scholar). by the of gene expression on The of as by in the or the in the studies the The that have of with the of this We for and E. J. and E. J. A. N. J. and W. A. N. J. and W. B. and E. J. A. N. J. and E. J. B. and E. J. B. and E. J. B. and E. J. We the of and E. and The is the of the and not the of the of

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