ReviewCell Biology

Cracking the context-specific PI3K signaling code

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Science Signaling  07 Jan 2020:
Vol. 13, Issue 613, eaay2940
DOI: 10.1126/scisignal.aay2940


  • Fig. 1 Simplified schematic of canonical class IA PI3K signaling and cellular outputs.

    Class IA PI3Ks exist as heterodimers composed of one of three catalytic subunits (p110α, p110β, or p110δ) bound to one of five regulatory subunits. They are commonly activated downstream of receptor tyrosine kinases when the regulatory subunit binds to phosphorylated tyrosine residues on the cytoplasmic domain of the receptor itself or associated adaptor proteins. The activation of individual PI3K isoforms may be enhanced further by RAS (PI3Kα and PI3Kδ), RAC/CDC42 (PI3Kβ), and/or G protein–coupled receptors (PI3Kβ). Once activated, class IA PI3Ks catalyze the formation of the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), which signals by binding to and recruiting effector proteins containing pleckstrin homology (PH) domains. Among these effectors, the AKT isoforms (AKT1/2/3) are involved in orchestrating key PI3K-dependent cellular phenotypes by acting on various cellular substrates, with some of the best characterized examples illustrated. These substrates also receive input from other pathways, and thus, the final phenotypic output is determined by context-dependent signal integration. Feedback loops are omitted for clarity.

  • Fig. 2 Information transmission in cell signaling.

    (A to D) Cells can respond to a signal’s rate (A) and duration (B); they can also respond to a signal’s strength (C) [amplitude modulation (AM)] or a signal’s temporal on/off pattern (D) [frequency modulation (FM)] (147149). Conversely, cells may also use similar changes in the dynamic activity of a shared set of intracellular components to encode the identity of the upstream stimulus (38, 55). (E) Example of low-fidelity signal transmission in cells with oncogenic RAS/ERK pathway activation. Altered dynamics in cells with specific BRAF variants result in misinterpretation of the upstream signal [adapted from (20)]. Similar corruption of information transmission, caused by enhanced BRAF-CRAF dimerization, has also been observed in response to the BRAF inhibitors SB590885 and vemurafenib (20).

  • Fig. 3 PIP3 dynamics encode distinct cellular responses.

    Using 3T3-L1 adipocytes stimulated with platelet-derived growth factor (PDGF) or insulin, Tengholm and Meyer demonstrated that cells may use different patterns of PIP3 dynamics to encode the identity of the upstream growth factor and subsequently decode these dynamics into different responses. Thus, insulin, but not PDGF, triggers translocation of intracellular GLUT4 storage vesicles to the plasma membrane and subsequent glucose uptake (42).

  • Fig. 4 Examples of dynamic information transmission in the class IA PI3K signaling pathway.

    (A) In the PC12 rat pheochromocytoma cell line, different patterns of epidermal growth factor receptor (EGFR) stimulation are transmitted differently to S6 kinase (S6K) downstream of AKT activation. Strong but transient EGFR stimulation is not transmitted efficiently from AKT through mTORC1 and S6K, representing a case of decoupled signal transfer in which the magnitude of the downstream response is opposite to that of the upstream signal. Instead, downstream S6 phosphorylation occurs most potently in response to weak but sustained EGFR activation. The EGFR kinase inhibitor lapatinib (dashed line) paradoxically enhances S6 phosphorylation by changing the dynamics of EGF-induced EGFR phosphorylation and activation. Adapted from (55). (B) Insulin levels in the blood oscillate according to specific patterns. These dynamic insulin changes are transmitted through phosphorylation of the insulin receptor and PI3K/AKT activation. Downstream, the different patterns of stimulation are selectively decoded through S6K and glycogen synthase kinase 3 (GSK3) phosphorylation as well as changes in G6P gene expression (38, 58). As a result, the activity of each component is in tune with different aspects of the upstream signal to elicit the most appropriate physiological response to insulin. Adapted from (58). Note that oscillations are not drawn to scale.

  • Fig. 5 Synthetic biology tools used in quantitative studies of PI3K signaling dynamics.

    (A) Reversible, chemically induced dimerization (CID) system used to modulate class IA PI3K signaling. It relies on the expression of a synthetic inter-SH2 (iSH2) construct of p85 interacting with the p110 catalytic subunit in an isoform-agnostic manner (150). Dimerization is induced by rCD1, a synthetic moiety that binds to both the SNAP tag at the plasma membrane and an FKBP fusion protein in the cytoplasm. The interaction can be reversed by addition of FK506 or an inert rapalog, both of which compete for binding to FKBP. (B) One of the first PI3K optogenetic (light-inducible) systems relied on the reversible light-induced interaction between phytochrome-interacting factor (PIF) and phytochrome (PHY) (151). Several other light-inducible PI3K systems have subsequently become available (152, 153). Note that both current CID and optogenetic approaches inevitably perturb the endogenous stoichiometry between p85 and p110, with likely consequences for downstream signaling output (5, 154). (C) Principle behind commonly used genetically encoded PIP3/PI(3,4)P2 biosensors. Different PH domains may bind either one or both lipid species, leading to translocation of the fluorescent reporter from the cytosol to the plasma membrane [for a comprehensive review on these sensors, see (64)]. (D) Fluorescent FOXO-based nucleocytoplasmic translocation reporters are commonly used in dynamic single-cell studies of PI3K signaling (62, 155157). However, FOXO proteins are only responsible for a subset of PI3K-dependent phenotypes (158).

  • Fig. 6 The context-specific PI3K signaling “tune”.

    Similar to the melody from an accordion, the output of PI3K signaling is shaped by the integration of multiple input parameters.


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