Signaling by Chemokine Receptors
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P139-140
2025-10-23
50
Chemokine receptors, just like other GPCRs, function as allosteric molecular relays where chemokine binding to the extracellular portion modifies the receptor’s tertiary structure. This allows the intracellular domain of the engaged receptor to bind to and activate heterotrimeric G proteins. In response, the activated G-proteins exchange GDP for GTP and in the process, dissociate into G α and G β γ subunits. Curiously, different chemokine receptors are able to associate with different subsets of G α subtypes, though any particular functional relevance of such biased signaling is not yet clear. The dissociated G β γ subunits mediate large parts of chemokine induced signals by activating different phosphatidylinositol 3-kinase (PI3K) isoforms, leading to the formation of phosphatidyl-3,4,5 triphosphate (PIP 3 ). PI3K and its product PIP 3 then translocate to the pseudopod at the leading edge of migrating leukocytes, where they colocalize with the small GTPase Rac. PIP 3 activates Rac through specific guanine nucleotide exchange factors. Rac in turn acts through the downstream effectors p21-activated kinase and the Wiskott-Aldrich protein homologue WAVE, which stimulate actin-related protein 2/3. Together, this process induces focal polymerization, required for the development and forward extension of the pseudopod, a critical step in leukocyte chemotaxis. The importance of PI3K-dependent signaling for leukocyte chemotaxis is evidenced by the lack of migration of myeloid leukocytes to chemokines in mice lacking PI3K γ Notably, though, distinct signaling pathways or at least other PI3K isoforms appear to be involved in the trafficking of immune cells. For example, neutrophil and B-cell migration requires PI3K δ , whereas T-cell chemotaxis is not impaired in PI3K-deficient mice, but depends on the Rac guanine exchange factor DOCK2.
Several pathways have been identified that can terminate chemokine signaling through their GPCRs. The G α subunit possesses an intrinsic GTPase activity to hydrolyze GTP. In a negative-feedback loop, this GTPase activity allows the G α subunits to reassociate with the G β γ subunits, thereby restoring the heterotrimeric G protein to its inactive state. In addition, another class of molecules, known as regulators of G protein signaling (RGS), also modulates signaling through chemokine GPCRs. RGS are a large and diverse protein family initially identified as GTPase-activating proteins of hetero trimeric G- protein G α -subunits.At least some RGS can also influence G α activity through either effector antagonism by competing with effector molecules for GTP-bound G α -subunits or by acting as guanine nucleotide dissociation inhibitors. To date, over three dozen genes have been identified within the human genome that encode proteins containing an RGS or RGS-like domain. Additionally, chemokine-induced receptor signaling is terminated by specific cytosolic enzymes known as GPCR kinases or GRKs.GRKs are able to rapidly phosphorylate the intracellular domains of the receptors thus, on one hand, abolishing G-protein-mediated signaling and, on the other hand, permitting the association of β -arrestins with the receptors. Such engagement of β -arrestins promotes the internalization of chemokine-triggered GPCRs from the cell membrane into intracellular vesicular compartments with the internalized chemokines targeted for lysosomal degradation and GPCRs either being also degraded or, alternatively, recycled back onto the cell membrane. Thus, pathways that involve GRKs and β -arrestins importantly mediate receptor “desensitization.” The activation of Src-family kinases downstream of the chemokine receptors via not yet fully mapped pathways involving G-proteins- and β -arrestins also contribute to the negative regulation of chemokine-induced migratory responses of myeloid cells. In addition to its well-documented role in shutting down chemokine receptor signaling and contributing to receptor desensitization, β -arrestins also play important roles in mediating some of the cellular effects downstream of chemokine receptors by triggering the activation of multiple intracellular molecular signals, thus “redirecting” signaling from G-proteins to the G-protein-independent pathways.
Remarkably, the molecular mechanisms involving RGS proteins and GRKs contributing to the “negative regulation” of chemokine signaling through their GPCRs might actually be required for optimal chemokine-induced in vitro and in vivo migratory leukocyte responses and their functions in host defense. A mutation (G184S) in G α i2 protein abolishes its interactions with RGS proteins, thus allowing it to continuously activate the downstream effectors. Neutrophils of mice with such (G184S) mutation showed enhanced rate base line locomotion but had reduced chemotactic responses in vitro and defective migratory responses in vivo.Analogously, neutrophils deficient of GRK2, the enzyme dominantly involved in desensitization of their chemotactic migration in response to swarming-inducing auto crinechemoattractants, migrated faster, hence covered larger field areas but were functionally less effective, e.g., in locating and killing bacteria.83
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