Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1α and MIP-1β on human monocytes
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Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2
This article has been cited by other articles in PMC.
Abstract
Monocyte
chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine
family, whose physiological function is mediated by binding to the CCR2
and CCR4 receptors, which are members of the G protein-coupled receptor
family. MCP-1 plays a critical role in both activation and migration of
leukocytes. Rapid chemokine receptor desensitization is very likely
essential for accurate chemotaxis. In this report, we show that MCP-1
binding to the CCR2 receptor in Mono Mac 1 cells promotes the rapid
desensitization of MCP-1-induced calcium flux responses. This
desensitization correlates with the Ser/Thr phosphorylation of the
receptor and with the transient translocation of the G protein-coupled
receptor kinase 2 (GRK2, also called β-adrenergic kinase 1 or βARK1) to
the membrane. We also demonstrate that GRK2 and the uncoupling protein
β-arrestin associate with the receptor, forming a macromolecular complex
shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293
cells expressing the CCR2B receptor were also markedly reduced upon
cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless,
expression of the GRK2 dominant-negative mutant βARK-K220R did not
affect the initial calcium response, but favored receptor response to a
subsequent challenge by agonists. The modulation of the CCR2B receptor
by GRK2 suggests an important role for this kinase in the regulation of
monocyte and lymphocyte response to chemokines.
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Proteasomal regulation of betac signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization.
Source
Baylor College of Medicine, Departments of Medicine and Immunology, Biology of Inflammation Center, Houston, Texas 77030, USA.Abstract
IL-5,
IL-3, and GM-CSF are hematopoietic cytokines that are key mediators of
the allergic inflammatory response. The receptors for these three
cytokines consist of a cytokine-specific alpha (Ralpha) chain and a
shared common beta (betac) chain. Herein, we demonstrate that agonistic
ligation of these receptor subunits rapidly induces proteasomal
degradation of the betac, but not the Ralpha, cytoplasmic domain,
resulting in termination of signal transduction and yielding a truncated
betac isoform ligated to the Ralpha subunit. Proteasomal degradation of
the betac cytoplasmic domain was also a prerequisite for endocytosis
and lysosomal degradation of the ligated receptor subunits. Moreover,
proteasome-dependent termination of signaling induced by one
betac-engaging cytokine resulted in cellular desensitization to signal
transduction by subsequent stimulation with another betac-engaging
cytokine. These data provide the first evidence for ligand-dependent
proteasomal degradation of the betac cytoplasmic domain, and they
establish a novel mechanism for heterotypic desensitization of shared
cytokine receptor signaling.
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Proteasomal regulation of βc signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization
This article has been cited by other articles in PMC.
Abstract
IL-5,
IL-3, and GM-CSF are hematopoietic cytokines that are key mediators of
the allergic inflammatory response. The receptors for these three
cytokines consist of a cytokine-specific α (Rα) chain and a shared
common β (βc) chain. Herein, we demonstrate that agonistic ligation of
these receptor subunits rapidly induces proteasomal degradation of the
βc, but not the Rα, cytoplasmic domain, resulting in termination of
signal transduction and yielding a truncated βc isoform ligated to the
Rα subunit. Proteasomal degradation of the βc cytoplasmic domain was
also a prerequisite for endocytosis and lysosomal degradation of the
ligated receptor subunits. Moreover, proteasome-dependent termination of
signaling induced by one βc-engaging cytokine resulted in cellular
desensitization to signal transduction by subsequent stimulation with
another βc-engaging cytokine. These data provide the first evidence for
ligand-dependent proteasomal degradation of the βc cytoplasmic domain,
and they establish a novel mechanism for heterotypic desensitization of
shared cytokine receptor signaling.
Collaborative role of E2F transcriptional activity and G1 cyclindependent kinase activity in the induction of S phase.
Source
Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.Abstract
A
considerable body of evidence points to a role for both cyclin
E/cyclin-dependent kinase (cdk)2 activity and E2F transcription activity
in the induction of S phase. We show that overexpression of cyclin
E/cdk2 in quiescent cells induces S phase, that this coincides with an
induction of E2F activity, and that coexpression of E2F enhances the
cyclin E/cdk2-mediated induction of S phase. Likewise, E2F
overexpression can induce S phase and does so in the apparent absence of
cyclin E/cdk2 activity. In addition, although the inhibition of cyclin
E/cdk2 activity blocks the induction of S phase after growth stimulation
of normal mouse embryo fibroblasts, inhibition of cyclin E/cdk2 does
not block S phase induction in Rb-/- cells where E2F activity is
deregulated. These results point to the important roles for E2F and
cyclin E/cdk2 in the induction of S phase. Moreover, the nature of the
E2F targets and the suspected targets for cyclin E/cdk2 suggests a
potential molecular mechanism for the collaborative action of cyclin
E/cdk2 and E2F in the induction of S phase.
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