While the activation of transcription factors is an important outcome of antigen receptor signaling, a productive T-cell response also requires substantial changes in cellular metabolism, needed to accommodate the energetic and macromolecular demands of rapidly dividing cells. The PI 3-kinase pathway plays a central role in this response via the recruitment and activation of the second important signaling module, initiated by the serine/threonine kinase Akt (also known as protein kinase B). Akt, via its PH domain, binds to PIP3 in the membrane, which is generated by PI 3-kinase (Fig. 7.22; see also Fig. 7.5). In that location, Akt is phosphorylated by PDK1, and once activated, phosphorylates a variety of downstream proteins. One of its effects is to promote cell survival by inhibiting cell death via multiple mechanisms. A major mechanism is the phosphorylation of the pro-apoptotic protein Bad. When phosphorylated, Bad can no longer bind to and inhibit the antiapoptotic (pro-survival) protein Bcl-2 (see Fig. 7.22). Another effect of activated Akt is to regulate the expression of homing and adhesion receptors that orchestrate the migratory properties of activated T cells (discussed in detail in Chapters 9 and 11). Activated Akt also functions to stimulate the cell’s metabolism by increasing the utilization of glucose; this is mediated by increasing the activity of glycolytic enzymes and by inducing the upregulation of nutrient transporters on the T-cell membrane.
Fig. 7.22 The serine/threonine kinase Akt is activated by TCR signaling and promotes cell survival and enhanced metabolic activity via mTOR. panel one: T-cell receptor (TcR) signaling activates pi 3-kinase (not shown), generating pip3 in the plasma membrane; pip3 recruits and activates the kinase pdK1. akt, a second serine/threonine kinase, binds to pip3 via its ph domain, and is phosphorylated and activated by pdK1. panel two: active akt phosphorylates the pro-apoptotic protein Bad, which is binding to and inhibiting the anti-apoptotic protein Bcl-2 at the mitochondrial membrane. panel three: phosphorylated Bad binds to 14-3-3, releasing Bcl-2 to promote cell survival. panel four: a second function of active akt is to phosphorylate the TSc1/2 complex, a Gap for the small GTpase Rheb. panel five: When TSc1/2 is phosphorylated, it releases the inactive Rheb protein, leading to Rheb activation. active Rheb binds to and activates mToR (mammalian target of rapamycin). once activated, mToR acts on multiple pathways that lead to increased lipid production, ribosome biosynthesis, mRna synthesis, and protein translation.
Akt Bcl-2 14-3-3 inactive Rheb active RhebTSC1/2 Bad outer mitochondrial membrane inner mitochondrial membrane matrix mTOR PDK1 lipid production ribosome biosynthesis mRNA synthesis protein translation PIP3 recruits PDK1 and Akt, allowing PDK1 to phosphorylate and activate Akt Active Akt phosphorylates Bad, releasing Bad from Bcl-2 Upon release, phosphorylated Bad binds 14-3-3, allowing Bcl-2 to promote cell survival Active Akt phosphorylates the TSC1/2 complex, a GAP for the small GTPase, Rheb Phosphorylated TSC1/2 releases Rheb, allowing active Rheb to bind mTOR
Fig. 7.23 Recruitment of ADAP to the LAT:Gads:SLP-76 complex activates integrin adhesion and aggregation.