PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting - PubMed (original) (raw)

Review

PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting

Lauren M Thorpe et al. Nat Rev Cancer. 2015 Jan.

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are crucial coordinators of intracellular signalling in response to extracellular stimuli. Hyperactivation of PI3K signalling cascades is one of the most common events in human cancers. In this Review, we discuss recent advances in our knowledge of the roles of specific PI3K isoforms in normal and oncogenic signalling, the different ways in which PI3K can be upregulated, and the current state and future potential of targeting this pathway in the clinic.

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Figures

Figure 1. The PI3K family comprises multiple classes and isoforms

PI3Ks are classified based on their substrate specificities and structures. In vivo, class IA and IB PI3Ks phosphorylate PtdIns(4,5)P2, while class III PI3Ks phosphorylate PtdIns. Some evidence suggests that class II PI3Ks may also preferentially phosphorylate PtdIns _in vivo_-. Class IA PI3Ks are heterodimers of a p110 catalytic subunit and a p85 regulatory subunit. Class IA catalytic isoforms (p110α, p110β, and p110δ) possess a p85-binding domain (p85-BD), RAS-binding domain (RBD), helical domain, and catalytic domain. Class IA p85 regulatory isoforms (p85α, p85β, p55α, p55γ, and p50α) possess an inter-SH2 (iSH2) domain that binds class IA catalytic subunits, flanked by SH2 domains that bind phosphorylated YXXM motifs. The longer isoforms, p85α and p85β, additionally possess N-terminal SH3 and breakpoint cluster homology (BH) domains. Class IB PI3Ks are heterodimers of a p110γ catalytic subunit and a p101 or p87 regulatory subunit. p110γ possesses an RBD, helical domain, and catalytic domain. The domain structures of p101 and p87 are not fully known, but a C-terminal region of p101 has been identified as binding Gβγ subunits. The monomeric class II isoforms (PI3K-C2α, PI3K-C2β, and PI3K-C2γ) possess an RBD, helical domain, and catalytic domain. VPS34, the only class III PI3K, possesses helical and catalytic domains. VPS34 forms a constitutive heterodimer with the myristoylated, membrane-associated VPS15 protein. Other indicated domains include proline-rich (P) domains and membrane-interacting C2 domains. Modified with permission from Reference 2.

Figure 2. Signaling by class I, II, and III PI3K isoforms

(A) Upon receptor tyrosine kinase (RTK) or G-protein coupled receptor (GPCR) activation, class I PI3Ks are recruited to the plasma membrane by interaction with phosphorylated YXXM motifs on RTKs or their adaptors, or with GPCR-associated Gβγ subunits. There they phosphorylate PtdIns(4,5)P2 (PIP2) to generate PtdIns(3,4,5)P3 (PIP3), a second messenger which activates a number of AKT-dependent and –independent downstream signaling pathways regulating diverse cellular functions including growth, metabolism, motility, survival, and transformation. The phosphatase and tensin homolog (PTEN) lipid phosphatase removes the 3′ phosphate from PtdIns(3,4,5)P3 to inactivate class I PI3K signaling. Modified with permission from Reference 2. (B) Class II PI3Ks are not well understood, but may be activated by a number of different stimuli, including hormones, growth factors, chemokines, cytokines, phospholipids, and calcium (Ca2+). Although in vitro class II PI3Ks can phosphorylate both PtdIns and PtdIns(4)P, in vivo this class may preferentially phosphorylate PtdIns (PI) to generate PtdIns(3)P (PIP)-. Class II PI3Ks regulate cellular functions including glucose transport, endocytosis, cell migration, and survival. Myotubularin (MTM) family phosphatases remove the 3′ phosphate from PtdIns(3)P to inactivate class II PI3K signaling. (C) The class III VPS34-VPS15 heterodimer is found in distinct multiprotein complexes, which perform specific cellular functions. VPS34 may be activated by stimuli including amino acids, glucose, and other nutrients, and phosphorylates PtdIns (PI) to generate PtdIns(3)P (PIP). It plays critical roles in autophagy, endosomal trafficking, and phagocytosis. MTM family phosphatases remove the 3′ phosphate from PtdIns(3)P to inactivate class III PI3K signaling.

Figure 2. Signaling by class I, II, and III PI3K isoforms

Figure 3. Divergent roles of class I PI3K catalytic isoforms in different signaling contexts

(A) Class I PI3Ks mediate signaling downstream of RTKs, GPCRs, and small GTPases. Left: p85 regulatory subunits bind phosphorylated YXXM motifs on activated RTKs. Because p110α, p110β, and p110δ bind p85, these isoforms mediate signaling downstream of RTKs. Recent evidence also suggests that p87-p110γ may be activated by certain RTKs. Middle: Small GTPases synergize with RTK and GPCR signals to directly activate PI3Ks by interacting with their RAS-binding domains (RBDs). Isoforms p110α, p110δ, and p110γ bind RAS family GTPases, while p110β binds the RHO family GTPases RAC1 and CDC42. _Right: G_α and Gβγ proteins dissociate from activated GPCRs. Catalytic isoforms p110β and p110γ, and regulatory isoform p101, directly bind and are activated by Gβγ. p110δ may be activated downstream of GPCRs, but the mechanism is unknown-. Gα proteins have been reported to directly bind and inhibit p110α-. Modified with permission from Reference 3. (B) Competition model for p110α and p110β regulation of RTK signaling. Both p85-p110α and p85-p110β compete for phosphorylated YXXM sites on activated RTKs. However, the maximal specific activity and enzymatic rate of p110α are higher than that of p110β, , and RTK-associated p110α may have higher lipid kinase activity than p110β. By this model, loss or inactivation of p110α or p110β differentially modulates RTK signaling. Knockout of p110α allows all sites to be occupied by the less active p110β, decreasing RTK output. Conversely, knockout of p110β allows all sites to be bound by the more active p110α, increasing RTK output. Genetically or pharmacologically inactivated p110α or p110β can still bind RTKs but cannot signal, reducing RTK output.

Figure 3. Divergent roles of class I PI3K catalytic isoforms in different signaling contexts

Figure 4. An overview of PI3K inhibitors and their combination with other therapeutics

(A) Molecular contexts dictating applications for isoform-selective PI3K inhibitors. Light orange boxes: Upregulation or mutation of receptor tyrosine kinases (RTKs), oncogenic RAS mutations, or activating p110α mutations all increase PtdIns(3,4,5)P3 production through p110α, which can be amplified by mutation or loss of PTEN. In these contexts use of p110α-selective inhibitors is effective. Blue boxes: In the absence of other oncogenic alterations, PTEN loss or mutation increases PtdIns(3,4,5)P3 production through p110β, perhaps due to RAC1- or CDC42-mediated p110β activation, or the basal activity of this isoform. In this context use of p110β-selective inhibitors is effective. Dark orange boxes: Upregulation or mutation of B cell receptors (BCRs), cytokine receptors, or other immune cell surface markers increases PtdIns(3,4,5)P3 production through p110δ. In this context use of p110δ-selective inhibitors is effective. (B) Rational combination of PI3K inhibitors and other targeted therapeutics. Pan-PI3K and dual pan-PI3K and mTOR inhibitors are currently being tested in clinical trials (white box). These agents are being combined with mTOR-selective inhibitors (shown in dark orange), RAS-RAF-MEK-ERK pathway inhibitors (shown in light orange), RTK (shown in grey) or other membrane-associated protein inhibitors (shown in turquoise), hormone signaling inhibitors (shown in dark blue), and other agents inhibiting the cell cycle, apoptosis machinery, or other signaling pathways (shown in purple). Colored symbols indicate targeted therapeutics currently in clinical trials for combination with the designated PI3K inhibitor. For further detail, see Supplementary Table 3.

Figure 4. An overview of PI3K inhibitors and their combination with other therapeutics

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PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting - PubMed (original) (raw)