The Role of mTOR Inhibitors for the Treatment of B-Cell Lymphomas

Figure 1

Molecular signaling cascades which normally control mTORC1 activity and may become dysregulated in B-cell lymphomas leading to aberrant mTORC1 signaling activation. The figure also demonstrates the functions of mTORC1 and mTORC2. (a) PI3K/Akt pathway: upon activation PI3K most possibly induces mTORC2 complex stimulation and also promotes the translocation of Akt and PDK1 to the cell membrane, where Akt becomes activated by PDK1 and mTORC2. Then, Akt activates mTORC1 by way of two mechanisms: (1) indirectly through downregulation of the inhibitory effect of the TSC1-TSC2 complex on Rheb protein and (2) directly through phosphorylation of PRAS40 (proline-rich Akt substrate of 40 kilodaltons), which is a component of the mTORC1 complex. The tumor suppressor phosphatases PTEN and SHIP oppose PI3K-mediated Akt activation. (b) RAF/MEK/ERK pathway: once activated this pathway triggers mTORC1 activity indirectly through inactivation of the TSC1-TSC2 complex by ERK and RSK (ribosomal S6 kinase, 90 kDa). The RAF/MEK/ERK pathway also directly activates mTORC1 through excitatory phosphorylation of raptor, a component of the mTORC1 complex, by RSK. (c) p38 is suggested to induce mTORC1 activity by acting downstream of or in parallel to Rheb. (d) PLD/phosphatidic acid (PA) pathway: upon activation PLD hydrolyzes phosphatidylcholine (PTDC) to generate choline (CHOL) and PA. Subsequently, PA activates mTORC1 by an unknown mechanism. (e) LKB1/AMP-dependent protein kinase (AMPK) pathway: the tumor suppressor kinase LKB1 activates AMP-dependent protein kinase (AMPK). AMPK, in turn, inhibits mTORC1 through activation of the TSC1-TSC2 complex and direct inhibitory phosphorylation of raptor.