Prokineticin-Receptor Network: Mechanisms of Regulation

Abstract

Prokineticins are a new class of chemokine-like peptides that bind their G protein-coupled receptors, PKR1 and PKR2, and promote chemotaxis and the production of pro-inflammatory cytokines following tissue injury or infection. This review summarizes the major cellular and biochemical mechanisms of prokineticins pathway regulation that, like other chemokines, include: genetic polymorphisms; mRNA splice modulation; expression regulation at transcriptional and post-transcriptional levels; prokineticins interactions with cell-surface glycosaminoglycans; PKRs degradation, localization, post-translational modifications and oligomerization; alternative signaling responses; binding to pharmacological inhibitors. Understanding these mechanisms, which together exert substantial biochemical control and greatly enhance the complexity of the prokineticin-receptor network, leads to novel opportunities for therapeutic intervention. In this way, besides targeting prokineticins or their receptors directly, it could be possible to indirectly influence their activity by modulating their expression and localization or blocking the downstream signaling pathways.

Keywords: GPCR; alternative splicing; binding; inhibitors; oligomerization; post-translational regulation; prokineticin receptors; prokineticins; transcriptional and post-transcriptional regulation.

Figure 1

Schematic representation of the pkr1 and pkr2 gene structure.

Figure 2

Schematic representation of the pk1 and pk2 gene structure.

Figure 3

Schematic overview of regulation mechanisms of the prokineticin receptors. GAG: proteoglycans; MVB: multivesicular body.