The PI3K Pathway in Human Disease David A. Fruman, Honyin Chiu, Benjamin D. Hopkins, Shubha Bagrodia, Lewis C. Cantley, Robert T. Abraham  Cell  Volume 170, Issue 4, Pages 605-635 (August 2017) DOI: 10.1016/j.cell.2017.07.029 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Overview of Phosphoinositides, Class I PI3K Protein Isoforms, p110α Activity Regulation, and PI3K Downstream Effectors (A) Schematic overview of the major synthesis and degradation pathways for PtdIns-3-P (PI3P), PtdIns-3,4-P2 and PtdIns-3,4,5-P3. The classes of PI3K (I, II, or III) that mediate reactions are indicated. Lipid phosphatases are in red. INPP4B, inositol polyphosphate-4-phosphatase, type II. (B) Domain structure of class I PI3K catalytic and regulatory subunits. ABD, adaptor-binding domain; RBD, Ras-binding domain; BH, breakpoint cluster region homology. (C) Diagram of the intramolecular interactions between class IA catalytic and regulatory subunits (p110α and p85α are displayed as well studied examples). Tight binding of the ABD to iSH2 confers stability to p110α. The other contacts shown in blue block arrows diminish basal activity and are relieved upon regulatory subunits binding to pTyr. Cancer-associated activating mutations are shown in green. SHORT syndrome mutation in p85α (R649W) is in purple. (D) Brief summary of key PI3K effectors: PDK-1, AKT, TEC family kinases, and GEFs/GAPs for small GTPases. AKT has many other important substrates not shown here (Manning and Toker, 2017). The specific GEFs that mediate PI3K-dependent Rac activation to promote motility and aldolase release are not known. Cell 2017 170, 605-635DOI: (10.1016/j.cell.2017.07.029) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Overview of mTORC1 and mTORC2 Complexes, Key Substrates, and Inhibitors The processes inhibited by different classes of mTOR inhibitor are shown. First-generation rapalogs are partial inhibitors of mTORC1 that inhibit phosphorylation of S6Ks more than 4E-BPs. Second-generation TORKi fully inhibit mTORC1 and mTORC2. Third-generation RapaLinks fully but selectively inhibit mTORC1 and also overcome single resistance mutations to rapalogs and TORKi. Cell 2017 170, 605-635DOI: (10.1016/j.cell.2017.07.029) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 3 Cartoon of Systemic Glucose Homeostasis in the Normal State and upon PI3K Inhibitor Treatment In the normal state, blood glucose levels are maintained in homeostasis through the actions of insulin, which stimulates glucose uptake and glycogen storage, thereby keeping the system balanced. Changes in blood glucose levels (such as increases upon eating) stimulate commensurate changes in insulin release that drive either increased glucose uptake (when insulin levels are high) or gluconeogenesis (when insulin levels are low). When PI3K inhibitors are used, they perturb insulin signaling in cells, thereby pushing the systemic balance to favor glucose release. This causes blood glucose levels to acutely increase, which in turn signals to the pancreas to release a bolus of insulin. As indicated by the cartoon, these high insulin levels have the potential to reactivate insulin signaling both in metabolic tissues, which is critical in order for the system to come back to homeostasis, as well as in tumors, where insulin has the potential to reactivate PI3K signaling, thereby undercutting the efficacy of the PI3K inhibitors. Cell 2017 170, 605-635DOI: (10.1016/j.cell.2017.07.029) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 4 Distinct Wiring of PI3K/mTOR Network in Lymphocytes (T and B Cells) Compared to Other Commonly Studied Non-lymphoid Cell Types such as Fibroblasts In lymphocytes, FOXO transcription factors have prominent roles in differentiation. mTORC1 is tightly coupled to nutrient access and often uncoupled from PI3K/AKT activity. Downstream of mTORC1, the 4E-BP/eIF4E axis controls both growth and proliferation, whereas in other cell types, S6Ks are crucial for cell growth. S6Ks might contribute to lymphocyte differentiation, but this is unproven. Cell 2017 170, 605-635DOI: (10.1016/j.cell.2017.07.029) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 5 Asymmetric Partitioning of PI3K/mTOR Signaling during Initial Division of Activated T and B Cells Results in Distinct Cell Fates of Daughter Cells This figure illustrates that the first division of activated lymphocytes produces two cells with differential levels of PI3K/mTOR signaling, which in turn drive distinct metabolic and differentiation programs. (Top) CD8 T cells. (Bottom) B cells. Cell 2017 170, 605-635DOI: (10.1016/j.cell.2017.07.029) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 6 Mechanisms of Adaptive, Primary, and Acquired Resistance to PI3K/mTOR Pathway Inhibitors Adaptive resistance (in green, also labeled “1”) often involves upregulation of upstream regulators, including RTKs (HER3, INSR, IGF-1R), IRS-1, JAK2, or SRC by disruption of negative-feedback loops. Primary or acquired resistance (in red, “2”) can arise by expression or activation of kinases with downstream targets in common with AKT or mTORC1 (SGK1, PDK1, PIM1), constitutive activation of mTORC1 signaling (e.g., due to loss of TSC function), or loss of PTEN expression. Primary or acquired resistance (in orange, “3”) can also arise by PI3K isoform switching; selective inhibition of p110α can lead to substitution by p110β or vice versa. Finally, primary or acquired resistance can also arise by activation of heterologous pathways leading to common endpoints; for instance, MYC-dependent transcriptional activation or ERK activity (in pink, “4”). Cell 2017 170, 605-635DOI: (10.1016/j.cell.2017.07.029) Copyright © 2017 Elsevier Inc. Terms and Conditions