Abstract
The generation of lipid products catalyzed by PI3K is critical for normal T cell homeostasis and a productive immune response. PI3K can be activated in response to antigen receptor, co-stimulatory, cytokine, and chemokine signals. Moreover, dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are also regulated by Akt, thus linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN, first identified as a tumor suppressor gene, encodes a lipid phosphatase that, by catalyzing the reverse of the PI3K “reaction,” directly opposes PI3K signaling. However, PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling. Through the use of models in which Pten is deleted specifically in T cells, it is becoming increasingly clear that control over autoimmunity and lymphomagenesis by PTEN involves multi-faceted functions of this molecule at multiple stages within the T cell compartment.
Highlights
Class 1A PI3Ks are directly linked to lymphocyte activation mainly through receptor tyrosine kinases, such as the antigen and cytokine receptors (Engelman et al, 2006; Huang and Sauer, 2010; So and Fruman, 2012)
Pten encodes a protein with a lipid phosphatase function that directly opposes PI3K signaling by dephosphorylating PIP3 at the 3 position to generate PIP2
Consistent with this, genomic amplification and mutation of either PI3K or Akt has been reported in a large number of cancers as well (Samuels et al, 2004; Lee et al, 2005; Carpten et al, 2007; Jaiswal et al, 2009), the role of PTEN as a tumor suppressor is believed to involve more than its ability to oppose PI3K signaling
Summary
PI3K can be activated in response to antigen receptor, co-stimulatory, cytokine, and chemokine signals. Dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are regulated by Akt, linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling.
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