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Regulation of PI-3-Kinase and Akt Signaling in T Lymphocytes and Other Cells by TNFR Family Molecules.

So T, Croft M - Front Immunol (2013)

Bottom Line: Accumulating evidence suggests that many members of the Tumor Necrosis Factor receptor (TNFR) superfamily, TNFR2 (TNFRSF1B), OX40 (TNFRSF4), 4-1BB (TNFRSF9), HVEM (TNFRSF14), and DR3 (TNFRSF25), that are constitutive or inducible on T cells, can directly or indirectly promote activity in the PI3K-Akt pathway.We discuss recent data which suggests that ligation of one TNFR family molecule organizes a signalosome, via TNFR-associated factor (TRAF) adapter proteins in T cell membrane lipid microdomains, that results in the subsequent accumulation of highly concentrated depots of PI3K and Akt in close proximity to TCR signaling units.We propose this may be a generalizable mechanism applicable to other TNFR family molecules that will result in a quantitative contribution of these signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine , Sendai , Japan.

ABSTRACT
Activation of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B) is a common response triggered by a range of membrane-bound receptors on many cell types. In T lymphocytes, the PI3K-Akt pathway promotes clonal expansion, differentiation, and survival of effector cells and suppresses the generation of regulatory T cells. PI3K activation is tightly controlled by signals through the T cell receptor (TCR) and the co-stimulatory receptor CD28, however sustained and periodic signals from additional co-receptors are now being recognized as critical contributors to the activation of this pathway. Accumulating evidence suggests that many members of the Tumor Necrosis Factor receptor (TNFR) superfamily, TNFR2 (TNFRSF1B), OX40 (TNFRSF4), 4-1BB (TNFRSF9), HVEM (TNFRSF14), and DR3 (TNFRSF25), that are constitutive or inducible on T cells, can directly or indirectly promote activity in the PI3K-Akt pathway. We discuss recent data which suggests that ligation of one TNFR family molecule organizes a signalosome, via TNFR-associated factor (TRAF) adapter proteins in T cell membrane lipid microdomains, that results in the subsequent accumulation of highly concentrated depots of PI3K and Akt in close proximity to TCR signaling units. We propose this may be a generalizable mechanism applicable to other TNFR family molecules that will result in a quantitative contribution of these signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR. We also review data that other TNFR molecules, such as CD40 (TNFRSF5), RANK (TNFRSF11A), FN14 (TNFRSF12A), TACI (TNFRSF13B), BAFFR (TNFRSF13C), and NGFR (TNFRSF16), contribute to the activation of this pathway in diverse cell types through a similar ability to recruit PI3K or Akt into their signaling complexes.

No MeSH data available.


Related in: MedlinePlus

Model of synergy between TCR/CD28 and TNFR signalosomes for activation of the PI3K-Akt pathway in T cells. T cells are activated firstly by recognition of antigen by the T cell receptor (TCR)/CD3 complex when it is displayed by the major histocompatibility complex (MHC) on antigen-presenting cells (APCs). The second co-stimulatory signal is delivered through CD28 by interaction with its ligands CD80 and/or CD86. These combined signals can activate phosphoinositide 3-kinase (PI3K), which leads to conversion of PIP2 into PIP3 at the plasma membrane. The pleckstrin homology (PH) domain containing proteins, Akt (protein kinase B) and phosphoinositide-dependent kinase 1 (PDK1), are recruited to the membrane PIP3, and then Akt is phosphorylated by PDK1 and by the mammalian target of rapamycin complex 2 (mTORC2). This promotes translocation of Akt from membrane to cytosol, thereby allowing regulation of downstream pathways through phosphorylation of target molecules, such as glycogen synthase kinase 3β (GSK3β), forkhead box O (Foxo), and IκB kinase (IKK). Akt phosphorylates and inactivates two negative regulators of mTORC1, tuberous sclerosis complex 2 (TSC2) and proline-rich Akt substrate of 40 kDa (PRAS40), which results in activation of mTORC1. Akt contributes to NF-κB activation through phosphorylation of IKK and interaction with protein kinase C θ (PKCθ) or caspase-recruitment domain (CARD)-membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1). After recognition of trimeric TNF ligand superfamily (TNFSF) molecules on APCs, TNF receptor superfamily (TNFRSF) molecules on T cells are trimerized and oligomerized and recruit trimeric TNFR-associated factors (TRAFs) to their cytoplasmic TRAF-binding motifs. The TNFSF-TNFRSF complex then translocates into detergent-insoluble membrane lipid microdomains (DIM). The TNFRSF-TRAF superclusters recruit and allow the efficient accumulation of PI3K and Akt in concentrated depots in close proximity to the TCR/CD28 signalosome, which results in a quantitative contribution of TNFR signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR/CD28 signalosome. The TNFR signalosomes also can promote activation of NF-κB irrespective of TCR/CD28 signaling. Red lines show activating signals, blue lines show inhibitory signals.
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Figure 2: Model of synergy between TCR/CD28 and TNFR signalosomes for activation of the PI3K-Akt pathway in T cells. T cells are activated firstly by recognition of antigen by the T cell receptor (TCR)/CD3 complex when it is displayed by the major histocompatibility complex (MHC) on antigen-presenting cells (APCs). The second co-stimulatory signal is delivered through CD28 by interaction with its ligands CD80 and/or CD86. These combined signals can activate phosphoinositide 3-kinase (PI3K), which leads to conversion of PIP2 into PIP3 at the plasma membrane. The pleckstrin homology (PH) domain containing proteins, Akt (protein kinase B) and phosphoinositide-dependent kinase 1 (PDK1), are recruited to the membrane PIP3, and then Akt is phosphorylated by PDK1 and by the mammalian target of rapamycin complex 2 (mTORC2). This promotes translocation of Akt from membrane to cytosol, thereby allowing regulation of downstream pathways through phosphorylation of target molecules, such as glycogen synthase kinase 3β (GSK3β), forkhead box O (Foxo), and IκB kinase (IKK). Akt phosphorylates and inactivates two negative regulators of mTORC1, tuberous sclerosis complex 2 (TSC2) and proline-rich Akt substrate of 40 kDa (PRAS40), which results in activation of mTORC1. Akt contributes to NF-κB activation through phosphorylation of IKK and interaction with protein kinase C θ (PKCθ) or caspase-recruitment domain (CARD)-membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1). After recognition of trimeric TNF ligand superfamily (TNFSF) molecules on APCs, TNF receptor superfamily (TNFRSF) molecules on T cells are trimerized and oligomerized and recruit trimeric TNFR-associated factors (TRAFs) to their cytoplasmic TRAF-binding motifs. The TNFSF-TNFRSF complex then translocates into detergent-insoluble membrane lipid microdomains (DIM). The TNFRSF-TRAF superclusters recruit and allow the efficient accumulation of PI3K and Akt in concentrated depots in close proximity to the TCR/CD28 signalosome, which results in a quantitative contribution of TNFR signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR/CD28 signalosome. The TNFR signalosomes also can promote activation of NF-κB irrespective of TCR/CD28 signaling. Red lines show activating signals, blue lines show inhibitory signals.

Mentions: Only studies of one molecule to date have shown a direct link of a TNFR family molecule to PI3K and Akt in T cells. However, there is strong rationale that the findings will be generalizable. We clearly demonstrated in several studies that OX40 signaling strongly synergizes with antigen signals to augment Akt activity in recently activated or effector T cells (Song et al., 2004; So et al., 2011a,b). After interaction of OX40 with transmembrane OX40L, OX40 moved into DIM and immunoprecipitation experiments revealed that it organized a signalosome containing many molecules including TRAF2, the IKK complex, and PKCθ and the CARMA1-BCL10-MALT1 complex, that regulate NF-κB1 activation, and also including p85 PI3K and Akt (So et al., 2011a,b). The formation of this complete OX40 signalosome in T cells was dependent on TRAF2 and on translocation of OX40 into DIM, but independent of antigen/TCR stimulation (So et al., 2011a,b). Moreover, in the absence of TRAF2 or by disrupting DIM, OX40 could not complex with either PI3K or Akt. Interestingly, OX40 was unable to induce significant cellular phosphorylation of PI3K, PIP3 accumulation, or Akt activation, unless antigen was presented to the T cells, even though antigen/TCR signaling had no obvious impact on recruitment of PI3K or Akt to the OX40 signalosome. The explanation for this was not clear, but we only found a moderate amount of PDK1 associated with the OX40 complex suggesting that this might in part contribute to the inability of OX40 ligation in isolation to lead to phosphorylation of Akt, and why antigen recognition was essential. However, more recent data have shown that OX40 associates with an E3 ligase that appears to limit its ability to activate Akt in T cells (Croft, unpublished). This then suggests that OX40 does possess the capacity to activate Akt independently of other receptors, but regulatory elements may keep this ability in check in T cells providing control over this aspect of OX40 biology to the TCR. Importantly, these data then imply that OX40 functions in T cells by quantitatively enhancing the amount of PI3K and Akt that is available to be activated in the lipid-rich microdomain environment. We hypothesize that the higher ordered oligomerized TNFR-ligand modules that are organized in DIM of T cells essentially offer functional hot spots of concentrated PI3K and Akt in the vicinity of the TCR/CD28 signalosome (Figure 2). These data also highlight that TRAF adaptors are likely to play critical roles in linking the TNFR family to PI3K and Akt in T cells. Our studies show that TRAF2 is important for OX40 to recruit both PI3K and Akt into its signaling complex, but whether TRAF2 directly binds one or both molecules is not yet clear. Other TRAFs, particularly TRAF6, may be also critical as described below in non-T cells, although how much this might vary from a T cell to another cell type is also not clear.


Regulation of PI-3-Kinase and Akt Signaling in T Lymphocytes and Other Cells by TNFR Family Molecules.

So T, Croft M - Front Immunol (2013)

Model of synergy between TCR/CD28 and TNFR signalosomes for activation of the PI3K-Akt pathway in T cells. T cells are activated firstly by recognition of antigen by the T cell receptor (TCR)/CD3 complex when it is displayed by the major histocompatibility complex (MHC) on antigen-presenting cells (APCs). The second co-stimulatory signal is delivered through CD28 by interaction with its ligands CD80 and/or CD86. These combined signals can activate phosphoinositide 3-kinase (PI3K), which leads to conversion of PIP2 into PIP3 at the plasma membrane. The pleckstrin homology (PH) domain containing proteins, Akt (protein kinase B) and phosphoinositide-dependent kinase 1 (PDK1), are recruited to the membrane PIP3, and then Akt is phosphorylated by PDK1 and by the mammalian target of rapamycin complex 2 (mTORC2). This promotes translocation of Akt from membrane to cytosol, thereby allowing regulation of downstream pathways through phosphorylation of target molecules, such as glycogen synthase kinase 3β (GSK3β), forkhead box O (Foxo), and IκB kinase (IKK). Akt phosphorylates and inactivates two negative regulators of mTORC1, tuberous sclerosis complex 2 (TSC2) and proline-rich Akt substrate of 40 kDa (PRAS40), which results in activation of mTORC1. Akt contributes to NF-κB activation through phosphorylation of IKK and interaction with protein kinase C θ (PKCθ) or caspase-recruitment domain (CARD)-membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1). After recognition of trimeric TNF ligand superfamily (TNFSF) molecules on APCs, TNF receptor superfamily (TNFRSF) molecules on T cells are trimerized and oligomerized and recruit trimeric TNFR-associated factors (TRAFs) to their cytoplasmic TRAF-binding motifs. The TNFSF-TNFRSF complex then translocates into detergent-insoluble membrane lipid microdomains (DIM). The TNFRSF-TRAF superclusters recruit and allow the efficient accumulation of PI3K and Akt in concentrated depots in close proximity to the TCR/CD28 signalosome, which results in a quantitative contribution of TNFR signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR/CD28 signalosome. The TNFR signalosomes also can promote activation of NF-κB irrespective of TCR/CD28 signaling. Red lines show activating signals, blue lines show inhibitory signals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 2: Model of synergy between TCR/CD28 and TNFR signalosomes for activation of the PI3K-Akt pathway in T cells. T cells are activated firstly by recognition of antigen by the T cell receptor (TCR)/CD3 complex when it is displayed by the major histocompatibility complex (MHC) on antigen-presenting cells (APCs). The second co-stimulatory signal is delivered through CD28 by interaction with its ligands CD80 and/or CD86. These combined signals can activate phosphoinositide 3-kinase (PI3K), which leads to conversion of PIP2 into PIP3 at the plasma membrane. The pleckstrin homology (PH) domain containing proteins, Akt (protein kinase B) and phosphoinositide-dependent kinase 1 (PDK1), are recruited to the membrane PIP3, and then Akt is phosphorylated by PDK1 and by the mammalian target of rapamycin complex 2 (mTORC2). This promotes translocation of Akt from membrane to cytosol, thereby allowing regulation of downstream pathways through phosphorylation of target molecules, such as glycogen synthase kinase 3β (GSK3β), forkhead box O (Foxo), and IκB kinase (IKK). Akt phosphorylates and inactivates two negative regulators of mTORC1, tuberous sclerosis complex 2 (TSC2) and proline-rich Akt substrate of 40 kDa (PRAS40), which results in activation of mTORC1. Akt contributes to NF-κB activation through phosphorylation of IKK and interaction with protein kinase C θ (PKCθ) or caspase-recruitment domain (CARD)-membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1). After recognition of trimeric TNF ligand superfamily (TNFSF) molecules on APCs, TNF receptor superfamily (TNFRSF) molecules on T cells are trimerized and oligomerized and recruit trimeric TNFR-associated factors (TRAFs) to their cytoplasmic TRAF-binding motifs. The TNFSF-TNFRSF complex then translocates into detergent-insoluble membrane lipid microdomains (DIM). The TNFRSF-TRAF superclusters recruit and allow the efficient accumulation of PI3K and Akt in concentrated depots in close proximity to the TCR/CD28 signalosome, which results in a quantitative contribution of TNFR signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR/CD28 signalosome. The TNFR signalosomes also can promote activation of NF-κB irrespective of TCR/CD28 signaling. Red lines show activating signals, blue lines show inhibitory signals.
Mentions: Only studies of one molecule to date have shown a direct link of a TNFR family molecule to PI3K and Akt in T cells. However, there is strong rationale that the findings will be generalizable. We clearly demonstrated in several studies that OX40 signaling strongly synergizes with antigen signals to augment Akt activity in recently activated or effector T cells (Song et al., 2004; So et al., 2011a,b). After interaction of OX40 with transmembrane OX40L, OX40 moved into DIM and immunoprecipitation experiments revealed that it organized a signalosome containing many molecules including TRAF2, the IKK complex, and PKCθ and the CARMA1-BCL10-MALT1 complex, that regulate NF-κB1 activation, and also including p85 PI3K and Akt (So et al., 2011a,b). The formation of this complete OX40 signalosome in T cells was dependent on TRAF2 and on translocation of OX40 into DIM, but independent of antigen/TCR stimulation (So et al., 2011a,b). Moreover, in the absence of TRAF2 or by disrupting DIM, OX40 could not complex with either PI3K or Akt. Interestingly, OX40 was unable to induce significant cellular phosphorylation of PI3K, PIP3 accumulation, or Akt activation, unless antigen was presented to the T cells, even though antigen/TCR signaling had no obvious impact on recruitment of PI3K or Akt to the OX40 signalosome. The explanation for this was not clear, but we only found a moderate amount of PDK1 associated with the OX40 complex suggesting that this might in part contribute to the inability of OX40 ligation in isolation to lead to phosphorylation of Akt, and why antigen recognition was essential. However, more recent data have shown that OX40 associates with an E3 ligase that appears to limit its ability to activate Akt in T cells (Croft, unpublished). This then suggests that OX40 does possess the capacity to activate Akt independently of other receptors, but regulatory elements may keep this ability in check in T cells providing control over this aspect of OX40 biology to the TCR. Importantly, these data then imply that OX40 functions in T cells by quantitatively enhancing the amount of PI3K and Akt that is available to be activated in the lipid-rich microdomain environment. We hypothesize that the higher ordered oligomerized TNFR-ligand modules that are organized in DIM of T cells essentially offer functional hot spots of concentrated PI3K and Akt in the vicinity of the TCR/CD28 signalosome (Figure 2). These data also highlight that TRAF adaptors are likely to play critical roles in linking the TNFR family to PI3K and Akt in T cells. Our studies show that TRAF2 is important for OX40 to recruit both PI3K and Akt into its signaling complex, but whether TRAF2 directly binds one or both molecules is not yet clear. Other TRAFs, particularly TRAF6, may be also critical as described below in non-T cells, although how much this might vary from a T cell to another cell type is also not clear.

Bottom Line: Accumulating evidence suggests that many members of the Tumor Necrosis Factor receptor (TNFR) superfamily, TNFR2 (TNFRSF1B), OX40 (TNFRSF4), 4-1BB (TNFRSF9), HVEM (TNFRSF14), and DR3 (TNFRSF25), that are constitutive or inducible on T cells, can directly or indirectly promote activity in the PI3K-Akt pathway.We discuss recent data which suggests that ligation of one TNFR family molecule organizes a signalosome, via TNFR-associated factor (TRAF) adapter proteins in T cell membrane lipid microdomains, that results in the subsequent accumulation of highly concentrated depots of PI3K and Akt in close proximity to TCR signaling units.We propose this may be a generalizable mechanism applicable to other TNFR family molecules that will result in a quantitative contribution of these signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine , Sendai , Japan.

ABSTRACT
Activation of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B) is a common response triggered by a range of membrane-bound receptors on many cell types. In T lymphocytes, the PI3K-Akt pathway promotes clonal expansion, differentiation, and survival of effector cells and suppresses the generation of regulatory T cells. PI3K activation is tightly controlled by signals through the T cell receptor (TCR) and the co-stimulatory receptor CD28, however sustained and periodic signals from additional co-receptors are now being recognized as critical contributors to the activation of this pathway. Accumulating evidence suggests that many members of the Tumor Necrosis Factor receptor (TNFR) superfamily, TNFR2 (TNFRSF1B), OX40 (TNFRSF4), 4-1BB (TNFRSF9), HVEM (TNFRSF14), and DR3 (TNFRSF25), that are constitutive or inducible on T cells, can directly or indirectly promote activity in the PI3K-Akt pathway. We discuss recent data which suggests that ligation of one TNFR family molecule organizes a signalosome, via TNFR-associated factor (TRAF) adapter proteins in T cell membrane lipid microdomains, that results in the subsequent accumulation of highly concentrated depots of PI3K and Akt in close proximity to TCR signaling units. We propose this may be a generalizable mechanism applicable to other TNFR family molecules that will result in a quantitative contribution of these signalosomes to enhancing and sustaining PI3K and Akt activation triggered by the TCR. We also review data that other TNFR molecules, such as CD40 (TNFRSF5), RANK (TNFRSF11A), FN14 (TNFRSF12A), TACI (TNFRSF13B), BAFFR (TNFRSF13C), and NGFR (TNFRSF16), contribute to the activation of this pathway in diverse cell types through a similar ability to recruit PI3K or Akt into their signaling complexes.

No MeSH data available.


Related in: MedlinePlus