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.
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Abbreviations
- AKT:
-
AKT serine/threonine kinase
- AML:
-
Acute myeloid leukemia
- APAF-1:
-
Apoptotic peptidase-activating factor-1
- B-ALL:
-
B-cell lymphoblastic leukemia/lymphoma
- BH3:
-
Bcl-2 homology 3
- CDK:
-
Cyclin-dependent kinase
- DISC:
-
Death-inducing signaling complex
- DUSP:
-
Dual-specificity phosphatase
- ERK:
-
Extracellular signal-regulated kinase
- FAP-1:
-
Fas-associated phosphatase-1
- Fas:
-
Fas cell surface death receptor
- FasL:
-
Fas ligand
- FCP:
-
F-cell production
- GAP:
-
GTPase-activating protein
- GEF:
-
Guanine nucleotide exchange factor
- GPCR:
-
G protein-coupled receptor
- GSK:
-
Glycogen synthase kinase
- JNK:
-
c-Jun NH2 terminal kinase
- KSR:
-
Kinase suppressor of Ras
- MAPK:
-
Mitogen-activated protein kinase
- MEK:
-
Mitogen-activated protein kinase kinase
- MEKK:
-
Mitogen-activated protein kinase kinase kinase
- MKP:
-
Mitogen-activated protein kinase phosphatase
- MNK:
-
Mitogen-activated protein kinase interacting serine/threonine kinase
- MOMP:
-
Mitochondrial outer membrane permeabilization
- MTA:
-
Microtubule-targeting agent
- MYC:
-
MYC proto-oncogene, basic helix-loop-helix transcription factor
- NF-κB:
-
Nuclear factor kappa B
- OA:
-
Okadaic acid
- PH:
-
Pleckstrin homology
- PHLPP:
-
Pleckstrin homology domain leucine-rich repeat protein phosphatase
- PI3K:
-
Phosphoinositol-3-kinase
- PIP2:
-
Phosphatidylinositol-4,5-biphosphate
- PIP3:
-
Phosphatidylinositol-3,4,5-triphosphate
- PIP:
-
Phosphatidylinositol phosphate
- PKC:
-
Protein kinase C
- PP1:
-
Protein phosphatase 1
- PP2A:
-
Protein phosphatase 2A
- PPM:
-
Metal-dependent protein phosphatase
- PPP:
-
Phosphoprotein phosphatase
- PSP:
-
Protein serine/threonine phosphatase
- PTEN:
-
Phosphatase and tensin homolog deleted on chromosome 10
- PTM:
-
Post-translational modification
- PTP:
-
Protein tyrosine phosphatase
- RTK:
-
Receptor tyrosine kinase
- SCP:
-
Small carboxy-terminal domain phosphatase
- SH2:
-
Src homology 2
- SOS:
-
Son of sevenless protein
- t-Bid:
-
Truncated Bid
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Narla, G., Sangodkar, J. & Ryder, C.B. The impact of phosphatases on proliferative and survival signaling in cancer. Cell. Mol. Life Sci. 75, 2695–2718 (2018). https://doi.org/10.1007/s00018-018-2826-8
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DOI: https://doi.org/10.1007/s00018-018-2826-8