1. PI3K/Akt/mTOR

PI3K/Akt/mTOR

PI3K/Akt/mTOR Signaling Pathway:

PI3K/Akt/mTOR

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Overview of PI3K/Akt/mTOR:

The PI3K/Akt/mTOR signaling pathways is crucial to many aspects of cell growth and survival, in physiological as well as in pathological conditions. PI3Ks constitute a lipid kinase family. Class I PI3Ks are heterodimers composed of a catalytic (CAT) subunit (i.e., p110) and an adaptor/regulatory subunit (i.e., p85), and can be further divided into two subclasses: subclass IA (PI3Kα, β, and δ), which is activated by receptors with protein tyrosine kinase activity, and subclass IB (PI3Kγ), which is activated by receptors coupled with G proteins. Akt kinases belong to the AGC kinase family, related to AMP/GMP kinases and protein kinase C. mTOR is a key protein evolutionarily conserved from yeast to man and is essential for life. The mTORC1 complex is made up of mTOR, Raptor, mLST8, and PRAS40, and the mTORC2 complex is composed of mTOR, Rictor, Sin1, and mLST8.

Upon ligand binding, phosphorylated tyrosine residing in activated RTKs will bind to p85, then release the catalytic subunit p110. Activated p110 phosphorylated the PIP2 into the second messenger PIP3, and this reaction can be reversed by the PI3K antagonist PTEN. PIP3 will recruit the downstream Akt to inner membranes and phosphorylates Akt on its serine/threonine kinase sites (Thr308 and Ser473). Activated Akt is involved in the downstream mTORC1 mediated response to biogenesis of protein and ribosome.

Many genes belonging to the PI3K/Akt pathway have been implicated in the pathophysiology of solid tumors and sensitivity/resistance to chemotherapy. More and more studies are now focusing on the translational relevance of targeting these pathways in cancer therapy.

 

References:

[1] Porta C, et al. Front Oncol. 2014 Apr 14;4:64.

[2] Follo MY, et al. Adv Biol Regul. 2015 Jan;57:10-6.

[3] Li X, et al. Oncotarget. 2016 May 31;7(22):33440-50.

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Phosphatidylinositol 3 kinases (PI3Ks) are a family of lipid kinases that integrate signals from growth factors, cytokines and other environmental cues, translating them into intracellular signals that regulate multiple signaling pathways. These pathways control many physiological functions and cellular processes, which include cell proliferation, growth, survival, motility and metabolism[1]

 

In the absence of activating signals, p85 interacts with p110 and inhibits p110 kinase activity. Following receptor tyrosine kinase (RTK) or G protein-coupled receptor (GPCR) activation, class I PI3Ks are recruited to the plasma membrane, where p85 inhibition of p110 is relieved and p110 phosphorylates PIP2 to generate PIP3. The activated insulin receptor recruits intracellular adaptor protein IRS1. Phosphorylation of IRS proteins on tyrosine residues by the insulin receptor initiates the recruitment and activation of PI3K. PIP3 acts as a second messenger which promotes the phosphorylation of Akt at Thr308 by PDK-1. RTK activation can also trigger Ras-Raf-MEK-ERK pathway. Activated Akt, ERK and RSK phosphorylate TSC2 at multiple sites to inhibit TSC1-TSC2-TBC1D7, which is the TSC complex that acts as a GTPase-activating protein (GAP) for the small GTPase RHEB. During inhibition of the TSC complex, GTP-loaded RHEB binds the mTOR catalytic domain to activate mTORC1. Glycogen synthase kinase 3β (GSK-3β) activates the TSC complex by phosphorylating TSC2 at Ser1379 and Ser1383. Phosphorylation of these two residues requires priming by AMPK-dependent phosphorylation of Ser1387. Wnt signaling inhibits GSK-3β and the TSC complex, and thus activates mTORC1. mTORC2 is activated by Wnt in a manner dependent on the small GTPase RAC1. Akt activation contributes to diverse cellular activities which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration. Important downstream targets of Akt are GSK-3, FOXOs, BAD, AS160, eNOS, and mTOR. mTORC1 negatively regulates autophagy through multiple inputs, including inhibitory phosphorylation of ULK1, and promotes protein synthesis through activation of the translation initiation promoter S6K and through inhibition of the inhibitory mRNA cap binding 4E-BP1[1][2][3].

 

PI3Kδ is a heterodimeric enzyme, typically composed of a p85α regulatory subunit and a p110δ catalytic subunit. In T cells, the TCR, the costimulatory receptor ICOS and the IL-2R can activate PI3Kδ. In B cells, PI3Kδ is activated upon crosslinking of the B cell receptor (BCR). The BCR co-opts the co-receptor CD19 or the adaptor B cell associated protein (BCAP), both of which have YXXM motifs to which the p85α SH2 domains can bind. In lumphocytes, BTK and ITK contribute to the activation of PLCγ and promotes the generation of DAG and the influx of Ca2+, which in turn activate PKC and the CARMA1-, BCL 10- and MALT1 containing (CBM) complex. The resulting NF-κB inhibitor kinase (IKK) activation leads to the phosphorylation and the degradation of IκB, and to the nuclear accumulation of the p50-p65 NF-κB heterodimer. MyD88 is an adapter protein that mediates signal transduction for most TLRs and leads to activation of PI3K[4].

 

Reference:

[1]. Thorpe LM, et al. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting.Nat Rev Cancer. 2015 Jan;15(1):7-24. 
[2]. Vanhaesebroeck B, et al. PI3K signalling: the path to discovery and understanding.Nat Rev Mol Cell Biol. 2012 Feb 23;13(3):195-203. 
[3]. Fruman DA, et al. The PI3K Pathway in Human Disease.Cell. 2017 Aug 10;170(4):605-635.
[4]. Lucas CL, et al. PI3Kδ and primary immunodeficiencies.Nat Rev Immunol. 2016 Nov;16(11):702-714.