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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

Tumor necrosis factor receptor family molecules that possibly activate the PI3K-Akt pathway in T cells. Molecular interactions between TNF receptor superfamily (TNFRSF) members and TNF ligand superfamily (TNFSF) members: TNFR2 (TNFRSF1B) and TNF (TNFSF2) or LTα (TNFSF1); OX40 (TNFRSF4) and OX40L (TNFSF4); CD27 (TNFRSF7) and CD70 (TNFSF7); CD30 (TNFRSF8) and CD30L (TNFSF8); 4-1BB (TNFRSF9) and 4-1BBL (TNFSF9); HVEM (TNFRSF14) and LIGHT (TNFSF14); GITR (TNFRSF18) and GITRL (TNFSF18); DR3 (TNFRSF25) and TL1A (TNFSF15). Interactions between TNFR-associated factors (TRAFs) and TNFRSF molecules are indicated in the inner circle. CD27, CD30, and GITR have yet to be described to promote activation of PI3K or Akt, but this is likely given their overlapping TRAF-binding capacity.
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Figure 1: Tumor necrosis factor receptor family molecules that possibly activate the PI3K-Akt pathway in T cells. Molecular interactions between TNF receptor superfamily (TNFRSF) members and TNF ligand superfamily (TNFSF) members: TNFR2 (TNFRSF1B) and TNF (TNFSF2) or LTα (TNFSF1); OX40 (TNFRSF4) and OX40L (TNFSF4); CD27 (TNFRSF7) and CD70 (TNFSF7); CD30 (TNFRSF8) and CD30L (TNFSF8); 4-1BB (TNFRSF9) and 4-1BBL (TNFSF9); HVEM (TNFRSF14) and LIGHT (TNFSF14); GITR (TNFRSF18) and GITRL (TNFSF18); DR3 (TNFRSF25) and TL1A (TNFSF15). Interactions between TNFR-associated factors (TRAFs) and TNFRSF molecules are indicated in the inner circle. CD27, CD30, and GITR have yet to be described to promote activation of PI3K or Akt, but this is likely given their overlapping TRAF-binding capacity.

Mentions: The range of membrane receptors that participate in triggering this PI3K/Akt axis in T cells may have been underappreciated. Recognition of antigen by the T cell receptor (TCR) in the context of signaling from the co-stimulatory receptor CD28 has long been known to promote PI3K activity. CD28 is constitutively expressed on T cells, and engagement by B7 molecules (CD80 and CD86) directly recruits the p85 regulatory subunit of PI3K (p85 PI3K) through a pYMNM (phospho-Tyr-Met-Asn-Met) motif located in CD28’s cytoplasmic tail (Pages et al., 1994). The overall signaling activity of CD28, including through the PI3K and Akt pathway, participates in the initial activation and division of T cells in many situations, although extensive studies have also suggested that the interaction with p85 is dispensable for many functions of CD28 in naïve T cells (Fruman and Bismuth, 2009). As well as CD28 and related molecules like ICOS, many additional receptors on T cells may contribute to PI3K and Akt activity. Sustained and periodic signaling from these receptors over time is increasingly being recognized as vital for continued T cell differentiation and survival, further suppression of Treg development, the generation of memory, and the reactivation of memory T cells. Members of the tumor necrosis factor receptor (TNFR) superfamily constitute many of these receptors (Croft, 2003, 2009; Watts, 2005; So et al., 2006). Although all of the TNFR family members discussed in this review are strong activators of NF-κB, and NF-κB certainly plays a role in many of the functional consequences of triggering these receptors, increasing evidence suggests that their ability to also target PI3K and Akt may be integral to their function. In T cells, these receptors include TNFR2 (TNFRSF1B), OX40 (TNFRSF4), 4-1BB (TNFRSF9), HVEM (TNFRSF14), and DR3 (TNFRSF25), which are either constitutively expressed or induced after activation (Figure 1). There are several other TNFR molecules that control T cell function, such as CD27 (TNFRSF7), CD30 (TNFRSF8), and GITR (TNFRSF18), that have yet to be described to promote activation of PI3K or Akt, however it is highly likely that they also have the ability to target this pathway (Figure 1). This review summarizes recent findings on the potential importance of TNFR family signaling in stimulating the PI3K-Akt pathway in T cells as well as in other cell types, and discusses the likely mechanism of how TNFR family molecules organize signalosomes on the membrane to sustain lipid signaling. The initial sections will present a brief overview of reported activities of TNFR family members on T cells that have been described to augment PI3K or Akt activity. We will then discuss the potential molecular connections that allow these molecules to link to PI3K or Akt, and lastly review PI3K and Akt related activation by other TNFR family members in non-T cells.


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)

Tumor necrosis factor receptor family molecules that possibly activate the PI3K-Akt pathway in T cells. Molecular interactions between TNF receptor superfamily (TNFRSF) members and TNF ligand superfamily (TNFSF) members: TNFR2 (TNFRSF1B) and TNF (TNFSF2) or LTα (TNFSF1); OX40 (TNFRSF4) and OX40L (TNFSF4); CD27 (TNFRSF7) and CD70 (TNFSF7); CD30 (TNFRSF8) and CD30L (TNFSF8); 4-1BB (TNFRSF9) and 4-1BBL (TNFSF9); HVEM (TNFRSF14) and LIGHT (TNFSF14); GITR (TNFRSF18) and GITRL (TNFSF18); DR3 (TNFRSF25) and TL1A (TNFSF15). Interactions between TNFR-associated factors (TRAFs) and TNFRSF molecules are indicated in the inner circle. CD27, CD30, and GITR have yet to be described to promote activation of PI3K or Akt, but this is likely given their overlapping TRAF-binding capacity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3675380&req=5

Figure 1: Tumor necrosis factor receptor family molecules that possibly activate the PI3K-Akt pathway in T cells. Molecular interactions between TNF receptor superfamily (TNFRSF) members and TNF ligand superfamily (TNFSF) members: TNFR2 (TNFRSF1B) and TNF (TNFSF2) or LTα (TNFSF1); OX40 (TNFRSF4) and OX40L (TNFSF4); CD27 (TNFRSF7) and CD70 (TNFSF7); CD30 (TNFRSF8) and CD30L (TNFSF8); 4-1BB (TNFRSF9) and 4-1BBL (TNFSF9); HVEM (TNFRSF14) and LIGHT (TNFSF14); GITR (TNFRSF18) and GITRL (TNFSF18); DR3 (TNFRSF25) and TL1A (TNFSF15). Interactions between TNFR-associated factors (TRAFs) and TNFRSF molecules are indicated in the inner circle. CD27, CD30, and GITR have yet to be described to promote activation of PI3K or Akt, but this is likely given their overlapping TRAF-binding capacity.
Mentions: The range of membrane receptors that participate in triggering this PI3K/Akt axis in T cells may have been underappreciated. Recognition of antigen by the T cell receptor (TCR) in the context of signaling from the co-stimulatory receptor CD28 has long been known to promote PI3K activity. CD28 is constitutively expressed on T cells, and engagement by B7 molecules (CD80 and CD86) directly recruits the p85 regulatory subunit of PI3K (p85 PI3K) through a pYMNM (phospho-Tyr-Met-Asn-Met) motif located in CD28’s cytoplasmic tail (Pages et al., 1994). The overall signaling activity of CD28, including through the PI3K and Akt pathway, participates in the initial activation and division of T cells in many situations, although extensive studies have also suggested that the interaction with p85 is dispensable for many functions of CD28 in naïve T cells (Fruman and Bismuth, 2009). As well as CD28 and related molecules like ICOS, many additional receptors on T cells may contribute to PI3K and Akt activity. Sustained and periodic signaling from these receptors over time is increasingly being recognized as vital for continued T cell differentiation and survival, further suppression of Treg development, the generation of memory, and the reactivation of memory T cells. Members of the tumor necrosis factor receptor (TNFR) superfamily constitute many of these receptors (Croft, 2003, 2009; Watts, 2005; So et al., 2006). Although all of the TNFR family members discussed in this review are strong activators of NF-κB, and NF-κB certainly plays a role in many of the functional consequences of triggering these receptors, increasing evidence suggests that their ability to also target PI3K and Akt may be integral to their function. In T cells, these receptors include TNFR2 (TNFRSF1B), OX40 (TNFRSF4), 4-1BB (TNFRSF9), HVEM (TNFRSF14), and DR3 (TNFRSF25), which are either constitutively expressed or induced after activation (Figure 1). There are several other TNFR molecules that control T cell function, such as CD27 (TNFRSF7), CD30 (TNFRSF8), and GITR (TNFRSF18), that have yet to be described to promote activation of PI3K or Akt, however it is highly likely that they also have the ability to target this pathway (Figure 1). This review summarizes recent findings on the potential importance of TNFR family signaling in stimulating the PI3K-Akt pathway in T cells as well as in other cell types, and discusses the likely mechanism of how TNFR family molecules organize signalosomes on the membrane to sustain lipid signaling. The initial sections will present a brief overview of reported activities of TNFR family members on T cells that have been described to augment PI3K or Akt activity. We will then discuss the potential molecular connections that allow these molecules to link to PI3K or Akt, and lastly review PI3K and Akt related activation by other TNFR family members in non-T cells.

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