Phosphoproteomic profiling of mouse primary HSPCs reveals new regulators of HSPC mobilization

Wang, Leo D.; Ficarro, Scott B.; Hutchinson, John N.; Csépányi-Kömi, Roland; Nguyen, Phi T.; Wisniewski, Éva; Sullivan, Jessica; Hofmann, Oliver; Ligeti, Erzsébet; Marto, Jarrod A.; Wagers, Amy J.

doi:10.1182/blood-2016-05-711424

Cited by 19 publications

(33 citation statements)

References 65 publications

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“…Applying a newly developed quantitative phosphoproteomic analysis, Leo Wang and his colleagues identified ARHGAP25 as a protein that showed highly different phosphorylation profiles in resting and mobilized hematopoietic stem and progenitor cells (HSPC). 27 They could also show that ARHGAP25 activity was essential for mobilization of hematopoietic cells from the bone marrow. Our group revealed that…”

Section: Smg-dependent Biological Processes?mentioning

confidence: 99%

The neglected terminators: Rho family GAPs in neutrophils

Csépányi-Kömi

Pásztor

Bartos

et al. 2018

Eur J Clin Investigation

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Background: GTPase-activating proteins (GAPs) accelerate the rate of hydrolysis of GTP bound to small GTPases, thereby limiting the prevalence and concentration of the active, GTP-bound form of these proteins. The large number of potential GAPs acting on members of the Rho family of small GTPases raises the question of specificity or redundancy. Results: In this review, we summarize experimental data obtained on the role of Rho family GAPs in neutrophils, highlight cases where more than one GAP is involved in a physiological function and show examples that GAPs can be involved not only in termination but also in initiation of cellular processes. We demonstrate that the expression-level regulation of GAPs may also occur in shortliving cells such as neutrophils. Finally, we provide insight into the existence and structure of molecular complexes in which Rho family GAPs are involved. Conclusion: GAPs play more complex and varied roles than being simple terminators of cellular processes. K E Y W O R D SGTPase activating proteins, Rho-family small GTPases, neutrophils

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Section: Smg-dependent Biological Processes?mentioning

confidence: 99%

The neglected terminators: Rho family GAPs in neutrophils

Csépányi-Kömi

Pásztor

Bartos

et al. 2018

Eur J Clin Investigation

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“…Our findings strongly suggest that the leukocytespecific RacGAP ARHGAP25 is a critical player in TNF-a-induced, Rac-mediated actin reorganization in neutrophils. Two recent reports provide important information on its physiological role: ARHGAP25 was shown to be required for actin depolymerization in the course of phagocytosis (21,44), and it was demonstrated to undergo significant changes in its phosphorylation pattern and GAP activity upon biological stimulation (45). TNF-a-initiated modulation of the phosphorylation pattern of ARHGAP25 with subsequent alterations of its GAP function may provide the link between the cytokine effect and the actin cytoskeleton rearrangement.…”

Section: Discussionmentioning

confidence: 99%

Rac GTPase Activating Protein ARHGAP25 Regulates Leukocyte Transendothelial Migration in Mice

Csépányi-Kömi

Wisniewski

Bartos

et al. 2016

The Journal of Immunology

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ARHGAP25 is a Rac-specific GTPase-activating protein that is expressed primarily in hematopoietic cells. The involvement of ARHGAP25 in regulating the recruitment of leukocytes to inflammatory sites was investigated in genetically modified mice. Using intravital microscopy, we show that Arhgap25 deficiency affects all steps of leukocyte recruitment with a predominant enhancement of transendothelial migration of neutrophilic granulocytes. Increased transmigration of Arhgap25-deficient leukocytes is demonstrated in inflamed cremaster muscle venules, in a peritonitis model, and in an in vitro chemotaxis assay. Using bone marrow chimeric mice lacking ARHGAP25 in the hematopoietic compartment, we show that enhanced migration in the absence of ARHGAP25 is due to defective leukocyte function. In search for potential mechanisms of ARHGAP25-regulated migration of neutrophils, we detected an increase in the amount of active, GTP-bound Rac and Rac-dependent cytoskeletal changes in the absence of ARHGAP25, suggesting a critical role of ARHGAP25 in counterbalancing the Rac-activating effect of nucleotide exchange factors. Taken together, using Arhgap25-deficient mice, we identified ARHGAP25 as a relevant negative regulator of leukocyte transendothelial migration.

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“…Moreover, inhibition of ARHGAP25 activity leads to augmented CXCL12 signaling. 84 In vivo, CXCL12 is truncated by the membranebound extracellular peptidase CD26 (dipeptidyl peptidase-4, DPP4), which is expressed on the surface of many cell types in the BM, including ECs and a subset of HPCs. 85,86 This peptidase is essential for G-CSF-induced HSPC mobilization, as Dpp4 −/mice show significantly decreased G-CSF-induced HSPC mobilization compared with wild-type mice.…”

Section: Integrins and The Cxcl12/cxcr4 Axis In Mobilizationmentioning

confidence: 99%

Cytokine‐induced hematopoietic stem and progenitor cell mobilization: unraveling interactions between stem cells and their niche

Kruijf

Fibbe

Pel

2019

Annals of the New York Academy of Sciences

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Peripheral blood hematopoietic stem and progenitor cells (HSPCs), mobilized by granulocyte colony-stimulating factor, are widely used as a source for both autologous and allogeneic stem cell transplantation. The use of mobilized HSPCs has several advantages over traditional bone marrow-derived HSPCs, including a less invasive harvesting process for the donor, higher HSPC yields, and faster hematopoietic reconstitution in the recipient. For years, the mechanisms by which cytokines and other agents mobilize HSPCs from the bone marrow were not fully understood. The field of stem cell mobilization research has advanced significantly over the past decade, with major breakthroughs in the elucidation of the complex mechanisms that underlie stem cell mobilization. In this review, we provide an overview of the events that underlie HSPC mobilization and address the relevant cellular and molecular components of the bone marrow niche. Furthermore, current and future mobilizing agents will be discussed.

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Phosphoproteomic profiling of mouse primary HSPCs reveals new regulators of HSPC mobilization

Abstract: Key Points Combining flow cytometry and high-performance mass spectrometry enables phosphoproteomic analysis of rare blood cell populations. ARHGAP25 dephosphorylation augments activity and promotes blood stem and progenitor cell mobilization by enhancing CXCL12 and Rac signaling.

Cited by 19 publications

References 65 publications

The neglected terminators: Rho family GAPs in neutrophils

The neglected terminators: Rho family GAPs in neutrophils

Rac GTPase Activating Protein ARHGAP25 Regulates Leukocyte Transendothelial Migration in Mice

Cytokine‐induced hematopoietic stem and progenitor cell mobilization: unraveling interactions between stem cells and their niche

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