Ligand-induced phosphorylation of the murine interleukin 3 receptor signals its cleavage.

Mui, Alice; Kay, RJ; Humphries, R. Keith; Krystal, Gerald

doi:10.1073/pnas.89.22.10812

Cited by 25 publications

(15 citation statements)

References 16 publications

(14 reference statements)

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“…An attractive hypothesis would be that Cis targets the Epo receptor for degradation. It has been previously reported that the degradation of the IL-3 receptor ␤ chain required its ligand-induced phosphorylation (45). This mechanism is consistent with the hypothesis that Cis, which binds to the tyrosine-phosphorylated Epo and IL-3 receptors, could be responsible for the degradation of these receptors and for the termination of the activation process.…”

Section: Discussionsupporting

confidence: 76%

Proteasomes Regulate Erythropoietin Receptor and Signal Transducer and Activator of Transcription 5 (STAT5) Activation

Verdier

Chrétien

Muller

et al. 1998

Journal of Biological Chemistry

178

144

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Cis is an Src homology 2 domain-containing protein, which binds to the erythropoietin receptor and decreases erythropoietin-stimulated cell proliferation. We show that Cis associates with the second tyrosine residue of the intracellular domain of the erythropoietin receptor (Tyr 401 ). Two forms of Cis with molecular masses of 32 and 37 kDa were detected, and we demonstrate that the 37-kDa protein resulted from post-translational modifications of the 32-kDa form. Anti-ubiquitin antibodies recognized the 37-kDa form of Cis and the proteasome inhibitors N-acetyl-leucyl-leucyl-norleucinal and lactacystin inhibited its degradation, showing that the 37-kDa form of Cis is a ubiquitinated protein, which seems to be rapidly degraded by the proteasome. In erythropoietin-stimulated UT-7 cells, the activation of the erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) was transient and returned to basal levels after 30 -60 min of erythropoietin stimulation. In contrast, these proteins remained strongly phosphorylated, and STAT5 remained activated for at least 120 min in the presence of proteasome inhibitors. These experiments demonstrate that the proteasomes are involved in the down-regulation of the erythropoietin receptor activation signals. Because the proteasome inhibitors induced the accumulation of both the ubiquitinated form of Cis and the Cis-erythropoietin receptor complexes, our results suggest that the ubiquitinated form of Cis could be involved in the proteasome-mediated inactivation of the erythropoietin receptor.

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Section: Discussionsupporting

confidence: 76%

Proteasomes Regulate Erythropoietin Receptor and Signal Transducer and Activator of Transcription 5 (STAT5) Activation

Verdier

Chrétien

Muller

et al. 1998

Journal of Biological Chemistry

178

144

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“…Previously, Mui et al (1992) reported that tyrosine phosphorylation of the IL3 receptor ,3 chain is the signal for its proteolytic cleavage to a 70 kDa fragment. The target molecule containing phosphotyrosine residues may become a substrate of the proteolytic machinery by binding to CIS.…”

Section: Discussionmentioning

confidence: 99%

A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors.

et al. 1995

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Cytokines manifest their function through alteration of gene expression. However, target genes for signals from cytokine receptors are largely unknown. We therefore searched for immediate‐early cytokine‐responsive genes and isolated a novel gene, CIS (cytokine inducible SH2‐containing protein) which is induced in hematopoietic cells by a subset of cytokines including interleukin 2 (IL2), IL3, granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and erythropoietin (EPO), but not by stem cell factor, granulocyte colony‐stimulating factor and IL6. The CIS message encodes a polypeptide of 257 amino acids that contains an SH2 domain of 96 amino acids in the middle. To clarify the function of CIS in cytokine signal transduction, we expressed CIS in IL3‐dependent hematopoietic cell lines under the control of a steroid‐inducible promoter. The CIS product stably associated with the tyrosine‐phosphorylated beta chain of the IL3 receptor as well as the tyrosine‐phosphorylated EPO receptor. Forced expression of CIS by steroid reduced the growth rate of these transformants, suggesting a negative role of CIS in signal transduction. CIS induction requires the membrane‐proximal region of the cytoplasmic domain of the EPO receptor as well as that of the common beta chain of the IL3, IL5 and GM‐CSF receptor, whereas CIS binds to the receptor that is tyrosine phosphorylated by cytokine stimulation. Thus CIS appears to be a unique regulatory molecule for cytokine signal transduction.

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“…The anti-c-Kit monoclonal antibody (MAb) was a generous gift from L. Ashman (University of Adelaide, Adelaide, Australia). Antibodies to the N-terminal 15 amino acids of the PIL-3 subunit of the murine IL-3 receptor (IL-3R) were produced by immunizing rabbits as described previously (30). Rabbit antisera to the human IL-3R Pc subunit and to the mouse Ep receptor (EpR) were generated by immunizing animals with glutathione S-transferase (GST) fusion proteins containing the entire intracellular domain of the human IL-3R c subunit (18) In a previous study we demonstrated that IL-3, SF, and Ep all induce the tyrosine phosphorylation of Shc and its association with Grb2 (8).…”

Section: Methodsmentioning

confidence: 99%

Multiple cytokines stimulate the binding of a common 145-kilodalton protein to Shc at the Grb2 recognition site of Shc.

et al. 1994

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We-recently reported that interleukin-3, Steel factor, and erythropoietin all induce the tyrosine phosphorylation of Shc and its association with Grb2 in hemopoietic cell lines. We have now further characterized the proteins that become associated with Shc following stimulation with these cytokines and found that, in response to all three, the tyrosine-phosphorylated form of Shc binds to common 145-and 52-kDa proteins which also become tyrosine phosphorylated in response to these growth factors. The 145-kDa protein, which appears, from antiphosphotyrosine blots of two-dimensional O'Farrell gels, to exist in four different phosphorylation states following cytokine stimulation (with isoelectric points ranging from 7.2 to 7.8), does not appear to be immunologically related to the subunit of the interleukin-3 receptor, c-Kit, BCR, ABL, JAKI, JAK2, Sosl, epsl5, or insulin receptor substrate 1 protein. Silver-stained sodium dodecyl sulfate gels indicate that the association of the 145-kDa protein with Shc occurs only after cytokine stimulation and that it can bind to the tyrosine-phosphorylated form of Shc in its non-tyrosine-phosphorylated state. The latter finding, in conjunction with the observations that p145 does not bind, in vitro, to the Src homology 2 (SH2) domain of Shc, that it is not present in anti-Grb2 immunoprecipitates, and that a phosphopeptide which blocks the binding of Shc to the SH2 domain of Grb2 also blocks the binding of Shc to p145, suggests that p145 contains an SH2 domain and competes with Grb2 for the same tyrosine-phosphorylated site on Shc. This implicates p145 as a potential regulator of Ras activity and, perhaps, of other as yet unidentified functions of Shc.

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Ligand-induced phosphorylation of the murine interleukin 3 receptor signals its cleavage.

Cited by 25 publications

References 16 publications

Proteasomes Regulate Erythropoietin Receptor and Signal Transducer and Activator of Transcription 5 (STAT5) Activation

Proteasomes Regulate Erythropoietin Receptor and Signal Transducer and Activator of Transcription 5 (STAT5) Activation

A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors.

Multiple cytokines stimulate the binding of a common 145-kilodalton protein to Shc at the Grb2 recognition site of Shc.

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