Phospholipase signalling networks in cancer

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Abstract

Phospholipases (PLC, PLD and PLA) are essential mediators of intracellular and intercellular signalling. They can function as phospholipid-hydrolysing enzymes that can generate many bioactive lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid and arachidonic acid. Lipid mediators generated by phospholipases regulate multiple cellular processes that can promote tumorigenesis, including proliferation, migration, invasion and angiogenesis. Although many individual phospholipases have been extensively studied, how phospholipases regulate diverse cancer-associated cellular processes and the interplay between different phospholipases have yet to be fully elucidated. A thorough understanding of the cancer-associated signalling networks of phospholipases is necessary to determine whether these enzymes can be targeted therapeutically.

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Figure 1: Overview of phospholipases.
Figure 2: Overview of phospholipase pathways and networks.
Figure 3: The role of phospholipases in tumorigenesis.

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Acknowledgements

The authors thank S.-H. Lee, K. Choi, S. K. Jang and H. M. Kwon for many useful discussions and suggestions for this article. They apologize to colleagues whose work could not be cited owing to space limitations. This work was supported by the grants (NRF-M1AXA002-2010-0029764, No.2010-0029434 and No.2012R1A2A1A03010110) of National Research Foundation and the grant (1210041-1) of National Cancer Center in Korea.

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Correspondence to Sung Ho Ryu.

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Supplementary information

Supplementary information Table S1

Phenotypes of phospholipase transgenic and knockout mice (XLSX 20 kb)

Supplementary information S2

Network analysis of phospholipases in cancer (PDF 161 kb)

Supplementary information S3

GOBP and GOCC of phospholipases and PLNs. (PDF 152 kb)

Supplementary information Table S4

Interactors and interactions of phospholipases and lipid meidators. (a) Interactors (XLS 238 kb)

Supplementary information S5

Expression profiles of phospholipases in cancer. (PDF 146 kb)

Supplementary information S6

Correlation of expression profiles across cancer types between phospholipases and PLNs. (PDF 341 kb)

Supplementary information S7

A hypothetical network delineating the relationships between phospholipases and their associated processes. (PDF 1149 kb)

Glossary

ApcMin mice

Mice that carry the multiple intestinal neoplasia (Min) point mutation at one Apc allele and that develop intestinal adenomas spontaneously. Commonly used model of human familial adenomatous polyposis and human sporadic colorectal cancer.

C2 domain

A structural domain that is involved in membrane targeting. The C2-like domain of calpain is superficially similar to the C2 domain of other enzymes.

Caveolae

Cholesterol-rich membrane microdomains that are stabilized by the caveolin proteins.

EF-hand domain

A structural domain responsible for calcium binding, found in calcium-binding proteins.

Intersegmental vessel

(ISV). A vessel that carries blood from the dorsal aorta between somites to the dorsal side of the neural tube.

Matrigel

The trade name for a gelatinous protein mixture that is secreted by mouse tumour cells. It resembles the complex extracellular environment found in many tissues and is commonly used as a three-dimensional matrix substrate for cell culture-based in vitro migration and invasion assays.

Phox homology (PX) domain

A phosphoinositide-binding domain that was found in the p40phox and p47phox domains of NADPH oxidase.

Pleckstrin homology (PH) domains

Sequences of approximately 100 amino acids that are present in many signalling molecules and that commonly bind to phospholipids and proteins.

Signal sequence

A short peptide chain that targets a protein to a specific location (for example, the extracellular region, mitochondria and nucleus).

sn-1 and sn-2 positions

To designate the configuration of glycerol derivatives, the carbon atoms of glycerol are numbered stereospecifically. Most fatty acids at the sn-1 position are saturated (palmitate or stearate), and the sn-2 acyl chain is a saturated fatty acid (oleic acids, linoleic acid, and arachidonic acid).

SH2 domain

SRC homology 2 domain. A protein–protein interaction domain capable of binding tyrosine phosphorylated sites.

SH3 domain

SRC homology 3 domain. A protein–protein interaction domain capable of binding proline-rich motifs.

Stress fibre

A contractile actin filament bundle that contains myosin II, which serves both as an F-actin bundling protein and as a force generator.

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