Three Lysine Residues in the Common β Chain of the Interleukin-5 Receptor Are Required for Janus Kinase (JAK)-dependent Receptor Ubiquitination, Endocytosis, and Signaling

Lei, Jonathan T.; Mazumdar, Tuhina; Martinez-Moczygemba, Margarita

doi:10.1074/jbc.m111.273482

Cited by 20 publications

(15 citation statements)

References 62 publications

(63 reference statements)

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“…Alternatively, increased JAK2 and LYN expression could be correlated with a negative feedback loop that down-regulates GM-CSFR ␤c levels in TF-1 cells. The ubiquitination of ␤c in response to IL-5 stimulation is dependent on JAK2 activity (68,69). In CBL-Y371H-and CBL-C384R-expressing cells, the enhanced JAK2 activity can potentially lead to increased ubiquitination of the ␤c by other ubiquitin ligases, resulting in decreased overall expression of the receptor subunit.…”

Section: Discussionmentioning

confidence: 99%

CBL Linker Region and RING Finger Mutations Lead to Enhanced Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Signaling via Elevated Levels of JAK2 and LYN

Javadi

Richmond

Huang

et al. 2013

Journal of Biological Chemistry

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Background: A subset of juvenile myelomonocytic leukemia (JMML) patients harbor mutations in the E3 ubiquitin ligase CBL. Results: CBL mutations result in increased GM-CSFR phosphorylation, elevated JAK2 and LYN levels, and enhanced survival. Conclusion: CBL JMML mutants display hypersensitive GM-CSF signaling that can be modulated via inhibition of JAK2 and/or SRC kinases. Significance: Mutation of CBL in JMML is associated with altered GM-CSF function.

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Section: Discussionmentioning

confidence: 99%

CBL Linker Region and RING Finger Mutations Lead to Enhanced Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Signaling via Elevated Levels of JAK2 and LYN

Javadi

Richmond

Huang

et al. 2013

Journal of Biological Chemistry

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“…Sorting of receptors into MVB provides intracellular signaling platforms and/or subsequent recycling of the receptor to the plasma membrane and/or leads to their lysosomal degradation (26). The importance of compartmentalized signaling has already been described for a number of other receptor systems, where ubiquitination and subsequent endocytosis of the receptors are needed for proper signal transduction (27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Cell Fate Decisions Regulated by K63 Ubiquitination of Tumor Necrosis Factor Receptor 1

Fritsch

Stephan

Tchikov

et al. 2014

Molecular and Cellular Biology

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Signaling by tumor necrosis factor (TNF) receptor 1 (TNF-R1), a prototypic member of the death receptor family, mediates pleiotropic biological outcomes ranging from inflammation and cell proliferation to cell death. Although many elements of specific signaling pathways have been identified, the main question of how these selective cell fate decisions are regulated is still unresolved. Here we identified TNF-induced K63 ubiquitination of TNF-R1 mediated by the ubiquitin ligase RNF8 as an early molecular checkpoint in the regulation of the decision between cell death and survival. Downmodulation of RNF8 prevented the ubiquitination of TNF-R1, blocked the internalization of the receptor, prevented the recruitment of the death-inducing signaling complex and the activation of caspase-8 and caspase-3/7, and reduced apoptotic cell death. Conversely, recruitment of the adaptor proteins TRADD, TRAF2, and RIP1 to TNF-R1, as well as activation of NF-B, was unimpeded and cell growth and proliferation were significantly enhanced in RNF8-deficient cells. Thus, K63 ubiquitination of TNF-R1 can be sensed as a new level of regulation of TNF-R1 signaling at the earliest stage after ligand binding. The cytokine tumor necrosis factor alpha (TNF-␣) is involved in a variety of cellular processes, such as inflammation, differentiation, control of cell proliferation, and initiation of apoptosis. TNF is known to bind to two receptors of the TNF receptor superfamily, TNF receptor 1 (TNF-R1) and TNF-R2. TNF-R1 is a member of the death receptor subgroup of this superfamily (1). The death receptors all have a death domain (DD) in the C-terminal tail that is necessary for activation of apoptosis. Selective recruitment of adaptor proteins to TNF-R1 decides whether nonapoptotic signaling pathways or cell death-inducing pathways will be initiated. Complex I is formed at the TNF-R1 DD by recruitment of TRADD, RIP1, TRAF2, and c-IAP1 (2). In the model of Micheau and Tschopp, induction of apoptosis is initiated by the ubiquitination of most complex I proteins, leading to their dissociation from TNF-R1. Binding of FADD to the DD of cytosolic TRADD facilitates the recruitment of caspase-8 and -10 via their DDs, forming complex II.Conflicting data exist regarding the complex formation that induces apoptosis after TNF stimulation. In contrast to the model described above (2), we previously reported that after recruitment of TRADD, RIP, and TRAF2 to TNF-R1 at the cell surface, the receptor is internalized and FADD and procaspase-8 are recruited, forming the death-inducing signaling complex (DISC) still associated with the TNF receptor at endosomal vesicles (TNF receptosomes) (3-5). Consecutively, caspase-8 is activated by autocleavage and induces caspase-3 activation either directly or indirectly via a mitochondrial amplification loop involving cytochrome c and APAF-1 release, forming the apoptosome with caspase-9.Recently, we found that within TNF receptosomes, caspase-8 activates caspase-7, which in turn cleaves A-SMase, initiating the production of...

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“…Previous studies have identified a cluster of three membrane-proximal GMRβc lysine residues (K457, K461 and K467) required for receptor-mediated ubiquitylation [10]. SOCS-1 mediated GMRβc ubiquitylation, which is stabilized and visualized in the presence of MG132, was markedly attenuated in GMRβc(3K>R) substitution mutant ( Fig.…”

Section: Resultsmentioning

confidence: 81%

“…Plasmids encoding Flag-SOCS-1, -2 and -3, SOCS-1▵SOCSBox have been previously described [11]. The triple lysine K>R mutant of βc, (K457R, K461R, K467R) [10] was generated using the QuikChange Site-Directed Mutagenesis Kit from Invitrogen (Burlington, ON, Canada) and the following primer pair: 5′-CTGCGCAGAAGGTGGGAGGAGAGGATCCCCAACCCCAGCAGGAGC …”

Section: Methodsmentioning

confidence: 99%

“…While the molecular mechanisms underlying GMR activation have been extensively studied [2], negative regulation of GMR signaling has been less explored. Martinez-Moczgyzemba and colleagues previously showed that the cytoplasmic domain of βc is ubiquitylated and degraded by the proteasome in response to stimulation by GM-CSF, IL-5 and IL-3 [8]–[10]; however, the ubiquitin ligase that targets βc for ubiquitin-mediated degradation remains unknown. Here, we identify suppressor of cytokine signaling 1 (SOCS-1) as an E3 ligase that binds to and ubiquitylates βc to promote its degradation via the 26S proteasome and attenuates GMR downstream signaling.…”

Section: Introductionmentioning

confidence: 99%

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SOCS-1 Mediates Ubiquitylation and Degradation of GM-CSF Receptor

et al. 2013

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) and the related cytokines interleukin (IL)-3 and IL-5 regulate the production and functional activation of hematopoietic cells. GM-CSF acts on monocytes/macrophages and granulocytes, and several chronic inflammatory diseases and a number of haematological malignancies such as Juvenile myelomonocytic leukaemia (JMML) are associated with deregulated GM-CSF receptor (GMR) signaling. The downregulation of GMR downstream signaling is mediated in part by the clearance of activated GMR via the proteasome, which is dependent on the ubiquitylation of βc signaling subunit of GMR via an unknown E3 ubiquitin ligase. Here, we show that suppressor of cytokine signaling 1 (SOCS-1), best known for its ability to promote ubiquitin-mediated degradation of the non-receptor tyrosine kinase Janus kinase 2 (JAK2), also targets GMRβc for ubiquitin-mediated degradation and attenuates GM-CSF-induced downstream signaling.

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Three Lysine Residues in the Common β Chain of the Interleukin-5 Receptor Are Required for Janus Kinase (JAK)-dependent Receptor Ubiquitination, Endocytosis, and Signaling

Cited by 20 publications

References 62 publications

CBL Linker Region and RING Finger Mutations Lead to Enhanced Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Signaling via Elevated Levels of JAK2 and LYN

CBL Linker Region and RING Finger Mutations Lead to Enhanced Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Signaling via Elevated Levels of JAK2 and LYN

Cell Fate Decisions Regulated by K63 Ubiquitination of Tumor Necrosis Factor Receptor 1

SOCS-1 Mediates Ubiquitylation and Degradation of GM-CSF Receptor

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