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1

Lysophosphatidic acids, cyclic phosphatidic acids and autotaxin as promissing targets in therapies of cancer and other diseases

100%

Gendaszewska-Darmach E.

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2008

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vol. 55

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issue 2

227-240

EN

Lysophospholipids have long been recognized as membrane phospholipid metabolites, but only recently lysophosphatidic acids (LPA) have been demonstrated to act on specific G protein-coupled receptors. The widespread expression of LPA receptors and coupling to several classes of G proteins allow LPA-dependent regulation of numerous processes, such as vascular development, neurogenesis, wound healing, immunity, and cancerogenesis. Lysophosphatidic acids have been found to induce many of the hallmarks of cancer including cellular processes such as proliferation, survival, migration, invasion, and neovascularization. Furthermore, autotaxin (ATX), the main enzyme converting lysophosphatidylcholine into LPA was identified as a tumor cell autocrine motility factor. On the other hand, cyclic phosphatidic acids (naturally occurring analogs of LPA generated by ATX) have anti-proliferative activity and inhibit tumor cell invasion and metastasis. Research achievements of the past decade suggest implementation of preclinical and clinical evaluation of LPA and its analogs, LPA receptors, as well as autotaxin as potential therapeutic targets.

2

Hypothetical orchestrated cooperation between dopaminergic and kinin receptors for the regulation of common functions

88%

Guevara-Lora I., Niewiarowska-Sendo A., Polit A., Kozik A.

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2016

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vol. 63

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issue 3

387-396

EN

The G protein-coupled receptors (GPCRs), one of the largest protein families, are essential components of the most commonly used signal-transduction systems in cells. These receptors, often using common pathways, may cooperate in the regulation of signal transmission to the cell nucleus. Recent scientific interests increasingly focus on the cooperation between these receptors, particularly in a context of their oligomerization, e.g. the formation of dimers that are able to change characteristic signaling of each receptor. Numerous studies on kinin and dopamine receptors which belong to this family of receptors have shown new facts demonstrating their direct interactions with other GPCRs. In this review, current knowledge on signaling pathways and oligomerization of these receptors has been summarized. Owing to the fact that kinin and dopamine receptors are widely expressed in cell membranes where they act as mediators of numerous common physiological processes, the information presented here sheds new light on a putative crosstalk of these receptors and provides more comprehensive understanding of possible direct interactions that may change their functions. The determination of such interactions may be useful for the development of new targeted therapeutic strategies against many disorders in which kinin and dopamine receptors are involved.

3

G protein-coupled receptors - recent advances

75%

Latek D., Modzelewska A., Trzaskowski B., Palczewski K., Filipek S.

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2012

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vol. 59

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issue 4

515-529

EN

The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of β2-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane α-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago.

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3 Acta Biochimica Polonica

1 2016

1 2012

1 2008

1 Filipek S.

1 Gendaszewska-Darmach E.

1 Guevara-Lora I.

1 Kozik A.

1 Latek D.

1 Modzelewska A.

1 Niewiarowska-Sendo A.

1 Palczewski K.

1 Polit A.

1 Trzaskowski B.

Lysophosphatidic acids, cyclic phosphatidic acids and autotaxin as promissing targets in therapies of cancer and other diseases

Hypothetical orchestrated cooperation between dopaminergic and kinin receptors for the regulation of common functions

G protein-coupled receptors - recent advances