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Review
. 2018 Aug;75(15):2695-2718.
doi: 10.1007/s00018-018-2826-8. Epub 2018 May 3.

The impact of phosphatases on proliferative and survival signaling in cancer

Goutham Narla  1 , Jaya Sangodkar  2 , Christopher B Ryder  3
Affiliations
Review

The impact of phosphatases on proliferative and survival signaling in cancer

Goutham Narla et al. Cell Mol Life Sci. 2018 Aug.

Abstract

The dynamic and stringent coordination of kinase and phosphatase activity controls a myriad of physiologic processes. Aberrations that disrupt the balance of this interplay represent the basis of numerous diseases. For a variety of reasons, early work in this area portrayed kinases as the dominant actors in these signaling events with phosphatases playing a secondary role. In oncology, these efforts led to breakthroughs that have dramatically altered the course of certain diseases and directed vast resources toward the development of additional kinase-targeted therapies. Yet, more recent scientific efforts have demonstrated a prominent and sometimes driving role for phosphatases across numerous malignancies. This maturation of the phosphatase field has brought with it the promise of further therapeutic advances in the field of oncology. In this review, we discuss the role of phosphatases in the regulation of cellular proliferation and survival signaling using the examples of the MAPK and PI3K/AKT pathways, c-Myc and the apoptosis machinery. Emphasis is placed on instances where these signaling networks are perturbed by dysregulation of specific phosphatases to favor growth and persistence of human cancer.

Keywords: Apoptosis; MAPK; PI3K; PP2A; Phosphorylation; c-Myc.

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Figures

Fig. 1
Fig. 1
Schematic representation of selected serine/threonine phosphatases, dual-specificity (DUSP) phosphatases, non-receptor protein tyrosine phosphatases and receptor tyrosine phosphatases. Several, but not all, important domains are depicted (see the legend at the bottom of the figure). For multi-subunit phosphatases, only the catalytic subunit is depicted. Among PSPs, note the difference in complexity between the catalytic subunits of multimeric PP2A and PP2B and the monomeric PHLPPs. CaM calmodulin; PDZ post-synaptic density protein 95, discs large homolog 1, zonula occludens-1
Fig. 2
Fig. 2
Control of the PI3K and RAS signaling pathways by phosphatase signaling. Phosphatases that target components of one or both pathways are shown in violet. Arrows denote activating, whereas bar-headed lines denote inhibitory effects. For simplicity, the intervening steps between stimulation of the various receptor types and PI3K/RAS pathway activation are not depicted. See text for further details. GPCR G protein-coupled receptor; RTK receptor tyrosine kinase
Fig. 3
Fig. 3
c-Myc regulation by post-translation modifications. Kinases are shown in green, phosphatases in magenta and the proline isomerase Pin1 is shown in lavender. The c-Myc trans/cis isomerization status at Pro63 is denoted by P63t/c; the two critical phosphorylation sites described in the text are denoted as T(Thr)58 and S(Ser)62. Dephosphorylation of GSK-3β by PP2A-B56δ activates the kinase to phosphorylate c-Myc at Thr58. Note the bolder transcriptional activation arrow associated with the doubly phosphorylated c-Myc, as this isoform is thought to have higher transcriptional activity. See text for further details
Fig. 4
Fig. 4
Apoptosis signaling pathway and its control by phosphorylation. Phosphorylation events that promote apoptosis are highlighted in green, while those that inhibit apoptosis are highlighted in red. Propagation of the apoptotic signal is denoted with an arrow. Inhibitory interactions are denoted with bar-headed lines (for example, t-Bid/BIM/PUMA inhibit the anti-apoptotic Bcl-2 proteins, whereas the anti-apoptotic Bcl-2 proteins inhibit Bax/Bak activation). The dotted rectangles represent groups of Bcl-2 family members with differential binding partners (i.e., Noxa preferentially binds to A1 and Mcl-1, whereas Bad/Bik/Bmf/Hrk bind more strongly to Bcl-2/Bcl-w/Bcl-xL). See text for further details on the involved kinases and phosphatases
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