Proteasomal regulation of βc signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization

Martinez-Moczygemba, Margarita; Huston, David P.

doi:10.1172/jci13877

Cited by 19 publications

(38 citation statements)

References 48 publications

(17 reference statements)

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“…75 Similar results were observed with all 3 βc-engaging cytokines. 75 Structurally, β IP contains the extracellular domain, the transmembrane domain, and a small part of its cytoplasmic domain. However, β IP is devoid of all tyrosine and serine phosphorylation because proteasomes degrade the large cytoplasmic domain containing all of these residues.…”

Section: Signal Terminationsupporting

confidence: 74%

“…[66][67][68][69][70][71][72][73][74][75] One mechanism is the activation of cytosolic tyrosine phosphatases that control the level of ligand-induced phosphorylated substrates. 66,67 The tyrosine phosphatase Src homology protein tyrosine phosphatase 1 (SHP1; also known as HCP, SHPTP1, and SHP) is involved in downregulating βc activation because its overexpression results in suppression of cell growth in response to IL-3.…”

Section: Signal Terminationmentioning

confidence: 99%

“…74,75 For βc, specific proteasome inhibitors revealed that after IL-5 ligation of its receptor, βc is downregulated by ubiquitination and proteasome degradation of its cytoplasmic domain, resulting in the generation of cytoplasmically truncated βc products termed βc intracytoplasmic proteolysis (β IP ; Fig 5). 75 Similar results were observed with all 3 βc-engaging cytokines. 75 Structurally, β IP contains the extracellular domain, the transmembrane domain, and a small part of its cytoplasmic domain.…”

Section: Signal Terminationmentioning

confidence: 99%

“…However, β IP is devoid of all tyrosine and serine phosphorylation because proteasomes degrade the large cytoplasmic domain containing all of these residues. 75 Moreover, inhibition of βc proteasome degradation results in prolonged activation of βc, JAK2, STAT5, and SHP2. 75 This observation suggested that activation of the ubiquitin proteasome pathway is a very rapid and efficient mechanism for complete termination of βc signal transduction.…”

Section: Signal Terminationmentioning

confidence: 99%

“…75 This downregulatory process results in transient heterotypic desensitization to other βc-engaging cytokines, thus preventing the stimulated cell from being further activated by more than one βc-engaging cytokine. This paradigm of heterotypic desensitization exists for each of the βc-engaging cytokines.…”

Section: Signal Terminationmentioning

confidence: 99%

See 4 more Smart Citations

Biology of common β receptor–signaling cytokines IL-3, IL-5, and GM-CSF

Martinez-Moczygemba

Huston

2003

Journal of Allergy and Clinical Immunology

226

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Section: Signal Terminationsupporting

confidence: 74%

Section: Signal Terminationmentioning

confidence: 99%

Section: Signal Terminationmentioning

confidence: 99%

Section: Signal Terminationmentioning

confidence: 99%

Section: Signal Terminationmentioning

confidence: 99%

See 3 more Smart Citations

Biology of common β receptor–signaling cytokines IL-3, IL-5, and GM-CSF

Martinez-Moczygemba

Huston

2003

Journal of Allergy and Clinical Immunology

226

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Cellular level models as tools for cytokine design

Radhakrishnan

Tidor

2010

Biotechnology Progress

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Cytokines and growth factors are critical regulators that connect intracellular and extracellular environments through binding to specific cell-surface receptors. They regulate a wide variety of immunological, growth, and inflammatory response processes. The overall signal initiated by a population of cytokine molecules over long time periods is controlled by the subtle interplay of binding, signaling, and trafficking kinetics. Building on the work of others, we abstract a simple kinetic model that captures relevant features from cytokine systems as well as related growth factor systems. We explore a large range of potential biochemical behaviors, through systematic examination of the model’s parameter space. Different rates for the same reaction topology lead to a dramatic range of biochemical network properties and outcomes. Evolution might productively explore varied and different portions of parameter space to create beneficial behaviors, and effective human therapeutic intervention might be achieved through altering network kinetic properties. Quantitative analysis of the results reveals the basis for tensions among a number of different network characteristics. For example, strong binding of cytokine to receptor can increase short-term receptor activation and signal initiation but decrease long-term signaling due to internalization and degradation. Further analysis reveals the role of specific biochemical processes in modulating such tensions. For instance, the kinetics of cytokine binding and receptor activation modulate whether ligand–receptor dissociation can generally occur prior to signal initiation or receptor internalization. Beyond analysis, the same models and model behaviors provide an important basis for the design of more potent cytokine therapeutics by providing insight into how binding kinetics affect ligand potency.

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Eliminative Signaling by Janus Kinases: Role in the Downregulation of Associated Receptors

Carbone

Fuchs

2013

J of Cellular Biochemistry

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Activation of cytokine receptor-associated Janus kinases (JAKs) mediates most, if not all, of the cellular responses to peptide hormones and cytokines. Consequently, JAKs play a paramount role in homeostasis and immunity. Members of this family of tyrosine kinases control the cytokine/hormone-induced alterations in cell gene expression program. This function is largely mediated through an ability to signal towards activation of the signal transducer and activator of transcription proteins (STAT) as well as towards some other pathways. Importantly, JAKs are also instrumental in tightly controlling the expression of associated cytokine and hormone receptors, and, accordingly, in regulating the cell sensitivity to these cytokines and hormones. This review highlights the enzymatic and non-enzymatic mechanisms of this regulation and discusses the importance of the ambidextrous nature of JAK as a key signaling node that integrates the combining the functions of forward signaling and eliminative signaling. Attention to the latter aspect of JAK function may contribute to emancipating our approaches to the pharmacologic modulation of JAKs.

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Proteasomal regulation of βc signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization

Cited by 19 publications

References 48 publications

Biology of common β receptor–signaling cytokines IL-3, IL-5, and GM-CSF

Biology of common β receptor–signaling cytokines IL-3, IL-5, and GM-CSF

Cellular level models as tools for cytokine design

Eliminative Signaling by Janus Kinases: Role in the Downregulation of Associated Receptors

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