Role of the proteasome in modulating native G-CSFR expression

Kindwall‐Keller, Tamila L.; Druhan, Lawrence J.; Ai, Jing; Hunter, Melissa; Massullo, Pam; Loveland, Megan; Avalos, Belinda R.

doi:10.1016/j.cyto.2008.04.015

Cited by 12 publications

(14 citation statements)

References 46 publications

(50 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have suggested roles for both the lysosome and proteasome in the related CSF receptor G-CSFR ligand-mediated internalization, 25 and for similar mechanisms to operate for the shared common chain. 18 However, we were unable to block GM-CSF-mediated GM-CSFR internalization nor GM-CSF mediated IL-8 release with MG132 (cell-permeable proteasome inhibitor), and likewise actinomycin D and brefeldin A had no effect on receptor internalization (Supplemental Fig.…”

Section: Measurement Of Gm-csfr Expression In Human Neutrophils Ismentioning

confidence: 99%

Neutrophil GM-CSF receptor dynamics in acute lung injury

Alessandris

Ferguson

Dodd

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

GM‐CSF is important in regulating acute, persistent neutrophilic inflammation in certain settings, including lung injury. Ligand binding induces rapid internalization of the GM‐CSF receptor (GM‐CSFRα) complex, a process essential for signaling. Whereas GM‐CSF controls many aspects of neutrophil biology, regulation of GM‐CSFRα expression is poorly understood, particularly the role of GM‐CSFRα in ligand clearance and whether signaling is sustained despite major down‐regulation of GM‐CSFRα surface expression. We established a quantitative assay of GM‐CSFRα surface expression and used this, together with selective anti‐GM‐CSFR antibodies, to define GM‐CSFRα kinetics in human neutrophils, and in murine blood and alveolar neutrophils in a lung injury model. Despite rapid sustained ligand‐induced GM‐CSFRα loss from the neutrophil surface, which persisted even following ligand removal, pro‐survival effects of GM‐CSF required ongoing ligand‐receptor interaction. Neutrophils recruited to the lungs following LPS challenge showed initially high mGM‐CSFRα expression, which along with mGM‐CSFRβ declined over 24 hr; this was associated with a transient increase in bronchoalveolar lavage fluid (BALF) mGM‐CSF concentration. Treating mice in an LPS challenge model with CAM‐3003, an anti‐mGM‐CSFRα mAb, inhibited inflammatory cell influx into the lung and maintained the level of BALF mGM‐CSF. Consistent with neutrophil consumption of GM‐CSF, human neutrophils depleted exogenous GM‐CSF, independent of protease activity. These data show that loss of membrane GM‐CSFRα following GM‐CSF exposure does not preclude sustained GM‐CSF/GM‐CSFRα signaling and that this receptor plays a key role in ligand clearance. Hence neutrophilic activation via GM‐CSFR may play an important role in neutrophilic lung inflammation even in the absence of high GM‐CSF levels or GM‐CSFRα expression.

show abstract

Section: Measurement Of Gm-csfr Expression In Human Neutrophils Ismentioning

confidence: 99%

Neutrophil GM-CSF receptor dynamics in acute lung injury

Alessandris

Ferguson

Dodd

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

show abstract

“…Interestingly, there is emerging evidence demonstrating the possible role of the ubiquitin/protease system in regulating G-CSFR expression [86]. Moreover, studies have demonstrated that ubiquitination is required for regulation of G-CSFR-mediated cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Aberrant regulation of FBW7 in cancer

Wang

Ye²,

Liu³

et al. 2014

Oncotarget

View full text Add to dashboard Cite

FBW7 (F-box and WD repeat domain-containing 7) or Fbxw7 is a tumor suppressor, which promotes the ubiquitination and subsequent degradation of numerous oncoproteins including Mcl-1, Cyclin E, Notch, c- Jun, and c-Myc. In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-δ, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p. Given that the Fbw7 tumor suppressor is frequently inactivated or deleted in various human cancers, targeting FBW7 regulators is a promising anti-cancer therapeutic strategy.

show abstract

“…In a recent study employing a temperature‐sensitive E1 expressing cell line (ts20), it was demonstrated that inhibition of E1 activity interferes with internalization of the G‐CSFR (38). These results suggest that internalization of the activated G‐CSFR requires an intact ubiquitination machinery.…”

Section: Resultsmentioning

confidence: 99%

Site‐Specific Ubiquitination Determines Lysosomal Sorting and Signal Attenuation of the Granulocyte Colony‐Stimulating Factor Receptor

Wölfler

Irandoust

Meenhuis

et al. 2009

Traffic

View full text Add to dashboard Cite

Ubiquitination of cytokine receptors controls intracellular receptor routing and signal duration, but the underlying molecular determinants are unclear. The suppressor of cytokine signaling protein SOCS3 drives lysosomal degradation of the granulocyte colony-stimulating factor receptor (G-CSFR), depending on SOCS3-mediated ubiquitination of a specific lysine located in a conserved juxtamembrane motif. Here, we show that, despite ubiquitination of other lysines, positioning of a lysine within the membrane-proximal region is indispensable for this process. Neither reallocation of the motif nor fusion of ubiquitin to the C-terminus of the G-CSFR could drive lysosomal routing. However, within this region, the lysine could be shifted 12 amino acids toward the Cterminus without losing its function, arguing against the existence of a linear sorting motif and demonstrating that positioning of the lysine relative to the SOCS3 docking site is flexible. G-CSFR ubiquitination peaked after endocytosis, was inhibited by methyl-β-cyclodextrin as well as hyperosmotic sucrose and severely reduced in internalization-defective G-CSFR mutants, indicating that ubiquitination mainly occurs at endosomes. Apart from elucidating structural and spatio-temporal aspects of SOCS3-mediated ubiquitination, these findings have implications for the abnormal signaling function of G-CSFR mutants found in severe congenital neutropenia, a hematopoietic disorder with a high leukemia risk.

show abstract

Role of the proteasome in modulating native G-CSFR expression

Cited by 12 publications

References 46 publications

Neutrophil GM-CSF receptor dynamics in acute lung injury

Neutrophil GM-CSF receptor dynamics in acute lung injury

Aberrant regulation of FBW7 in cancer

Site‐Specific Ubiquitination Determines Lysosomal Sorting and Signal Attenuation of the Granulocyte Colony‐Stimulating Factor Receptor

Contact Info

Product

Resources

About