Novel role of WD40 and SOCS box protein-2 in steady-state distribution of granulocyte colony-stimulating factor receptor and G-CSF-controlled proliferation and differentiation signaling

Erkeland, Stefan J.; Aarts, Lambertus H. J.; Irandoust, Mahban; Roovers, Onno; Klomp, Adriana E.; Valkhof, Marijke; Gits, Judith; Eyckerman, Sven; Tavernier, Jan; Touw, Ivo P.

doi:10.1038/sj.onc.1210004

Cited by 21 publications

(17 citation statements)

References 41 publications

(30 reference statements)

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“…Our results differ from a recent study by Erkeland et al [27], who reported a lack of reactivity of the ubiquitinated murine G-CSFR with the FK2 antibody. The reasons for the discrepancy are not readily apparent but could relate to the different cell lines used by these investigators or inherent differences in ligand-induced modifications of murine versus human G-CSFR.…”

Section: Discussioncontrasting

confidence: 99%

“…Irandoust et al previously reported that mutation of all five G-CSFR cytoplasmic lysines to arginine had no effect on ligand-induced internaliaztion, arguing against a direct mechanism [26]. This observation along with our own findings here suggest the G-CSFR like the GHR [27] undergoes ubiquitination dependent ligand-induced internalization through an indirect mechanism. Such a mechanism is consistent with the involvement of an accessory protein(s) that interacts with the G-CSFR at a site distal to residue 716.…”

Section: Discussionsupporting

confidence: 74%

“…Our finding that chloroquine inhibits ligandinduced degradation of the WR G-CSFR supports a role for ubiquitination in routing the G-CSFR in transfected ts20 cells through the endocytic pathway for delivery to lysosomes, and is consistent with the report by Erkeland et al [27] However, our observations with MG132 and the FK2 antibody also support a role for proteasomes in addition to lysosomes in degradation of the activated G-CSFR in ts20 cells. Thus, the region that is deleted in the Δ716 mutant appears to mediate both ubiquitination-dependent internalization of the activated G-CSFR and intracellular sorting of the ubiquitinated G-CSFR species.…”

Section: Discussionsupporting

confidence: 68%

“…Endocytosis and lysosomal degradation of the GHR was shown to require an active ubiquitin/proteasome system, while the role of the ubiquitin/ proteasome system in internalization and lysosomal routing of the IL-2R remains controversial. Recent studies of the murine G-CSFR indicate it is also ubiquitnated and sorted to the lysosome [26,27].…”

Section: Introductionmentioning

confidence: 99%

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Role of the proteasome in modulating native G-CSFR expression

Kindwall‐Keller

Druhan

et al. 2008

Cytokine

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The granulocyte colony-stimulating factor receptor (G-CSFR) is a critical regulator of granulopoiesis, but the mechanisms controlling its surface expression are poorly understood. Recent studies using transfected cell lines have suggested the activated G-CSFR is routed to the lysosome and not the proteasome. Here, we examined the role of the ubiquitin/proteasome system in regulating G-CSFR surface expression in both ts20 cells that have a temperature-sensitive E1 ubiquitinactivating enzyme and in primary human neutrophils. We show that the G-CSFR is constitutively ubiquitinated, which increases following ligand binding. In the absence of a functional E1 enzyme, ligand-induced internalization of the receptor is inhibited. Pre-treatment of ts20 transfectants with either chloroquine or MG132 inhibited ligand-induced G-CSFR degradation, suggesting a role for both lysosomes and proteasomes in regulating G-CSFR surface expression in this cell line. In neutrophils, inhibition of the proteasome but not the lysosome was found to inhibit internalization/ degradation of the activated G-CSFR. Collectively, these data demonstrate the requirement for a functional ubiquitin/proteasome system in G-CSFR internalization and degradation. Our results suggest a prominent role for the proteasome in physiologic modulation of the G-CSFR, and provide further evidence for the importance of the ubiquitin/proteasome system in the initiation of negative signaling by cytokine receptors.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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Role of the proteasome in modulating native G-CSFR expression

Kindwall‐Keller

Druhan

et al. 2008

Cytokine

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“…This function is contingent on the SOCS box and lysines in the final 13 residues of the receptor tail; G-CSF-R mutants lacking this region show an impaired proliferative response to G-CSF both in vivo and in vitro (76). Potential targets with evidence of SOCS box-mediated ubiquitination are listed in Table 1.…”

Section: Wd40 and Socs Box Protein Substratesmentioning

confidence: 99%

The SOCS box—Adapting proteins for ubiquitination and proteasomal degradation

2012

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SummaryThe suppressor of cytokine signalling (SOCS) box was first identified in the SH2-containing SOCS box family (cytokine-inducible SH2-containing protein, SOCS1-7) and is a 40-amino acid motif, which functions to recruit an E3 ubiquitin ligase complex consisting of the adapter proteins elongins B and C, Rbx2 and the scaffold protein Cullin5. The SOCS box is found in a diverse array of intracellular signalling molecules, many of which contain different protein interaction domains such as SPRY and WD40 domains, leucine and ankyrin repeats or other functional domains such as GTPases. In general, the SOCS box-containing proteins are thought to act as substrate-recognition modules to mediate the polyubiquitination and subsequent degradation of substrate proteins by the 26S proteasome.

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E3 ubiquitin ligase Fbw7 negatively regulates granulocytic differentiation by targeting G-CSFR for degradation

Lochab

Pal

Kapoor

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Tight control between activation and attenuation of granulocyte colony stimulating factor receptor (G-CSFR) signaling is essential to regulate survival, proliferation and differentiation of myeloid progenitor cells. Previous studies demonstrated negative regulation of G-CSFR through endosomal-lysosomal routing and ubiquitin-proteasome mediated degradation. However, very few E3 ubiquitin ligases are known to target G-CSFR for ubiquitin-proteasome pathway. Here we identified F-box and WD repeat domain-containing 7 (Fbw7), a substrate recognizing component of Skp-Cullin-F box (SCF) E3 ubiquitin Ligase physically associates with G-CSFR and promotes its ubiquitin-mediated proteasomal degradation. Our data shows that Fbw7 also interacts with and degrades G-CSFR-T718 (a truncated mutant of G-CSFR found in severe congenital neutropenia/acute myeloid leukemia (SCN/AML patients)) though at a quite slower rate compared to G-CSFR. We further show that glycogen synthase kinase 3 beta (GSK3β), like Fbw7 also targets G-CSFR and G-CSFR-T718 for degradation; however, Fbw7 and GSK3β are interdependent in targeting G-CSFR/G-CSFR-T718 for degradation because they are unable to degrade G-CSFR individually when either of them is knocked down. We further show that Fbw7 mediated downregulation of G-CSFR inhibits signal transducer and activator of transcription 3 (STAT3) phosphorylation which is required for G-CSF dependent granulocytic differentiation. In addition, our data also shows that inhibition of Fbw7 restores G-CSFR signaling leading to enhanced STAT3 activity resulting in massive granulocytic differentiation. These data indicate that Fbw7 together with GSK3β negatively regulates G-CSFR expression and its downstream signaling.

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Novel role of WD40 and SOCS box protein-2 in steady-state distribution of granulocyte colony-stimulating factor receptor and G-CSF-controlled proliferation and differentiation signaling

Cited by 21 publications

References 41 publications

Role of the proteasome in modulating native G-CSFR expression

Role of the proteasome in modulating native G-CSFR expression

The SOCS box—Adapting proteins for ubiquitination and proteasomal degradation

E3 ubiquitin ligase Fbw7 negatively regulates granulocytic differentiation by targeting G-CSFR for degradation

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