R-Ras and Rac GTPase Cross-talk Regulates Hematopoietic Progenitor Cell Migration, Homing, and Mobilization

Shang, Xun; Cancelas, José A.; Li, Lina; Guo, Fukun; Liu, Wei; Johnson, J. F.; Ficker, Ashley; Daria, Deidre; Geiger, Hartmut; Ratner, Nancy; Zheng, Yi

doi:10.1074/jbc.m111.226951

Cited by 17 publications

(18 citation statements)

References 40 publications

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“…S1B). Another possibility could be an intrinsic migration defect of Rras -deficient CD4 T cells, since a role for R-Ras in cellular migration has been shown (4, 48). To address this question, we generated mixed BM chimera mice by transplanting an equal mix of WT (CD45.1) and Rras −/− (CD45.2) BM into lethally irradiated recipient mice.…”

Section: Resultsmentioning

confidence: 99%

An Increase in Tolerogenic Dendritic Cell and Natural Regulatory T Cell Numbers during Experimental Autoimmune Encephalomyelitis in Rras−/− Mice Results in Attenuated Disease

Ray

Basu

Miller

et al. 2014

The Journal of Immunology

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R-Ras is a member of the Ras superfamily of small GTPases, which are regulators of various cellular processes including adhesion, survival, proliferation, trafficking and cytokine production. R-Ras is expressed by immune cells and has been shown to modulate DC function in vitro and has been associated with liver autoimmunity. We used Rras-deficient mice to study the mechanism whereby R-Ras contributes to autoimmunity using experimental autoimmune encephalomyelitis (EAE), a mouse model of the CNS autoimmune disease multiple sclerosis (MS). We found that a lack of R-Ras in peripheral immune cells resulted in attenuated EAE disease. Further investigation revealed that during EAE, absence of R-Ras promoted the formation of MHC IIlo DC concomitant with a significant increase in proliferation of natural T regulatory cells (nTreg) resulting in an increase in their cell numbers in the periphery. Our study suggests a novel role for R-Ras in promoting autoimmunity through negative regulation of nTreg numbers by inhibiting the development of MHCIIlo DC with tolerogenic potential.

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Section: Resultsmentioning

confidence: 99%

An Increase in Tolerogenic Dendritic Cell and Natural Regulatory T Cell Numbers during Experimental Autoimmune Encephalomyelitis in Rras−/− Mice Results in Attenuated Disease

Ray

Basu

Miller

et al. 2014

The Journal of Immunology

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“…6). Yet, it was possible to see that RAS double-mutant JMML had the most severe presentation, with an increase in the number of blasts in the bone marrow (≥10%) in nine of 13 As in supplementary table 5, additional somatic alterations were defined as somatically acquired mutations other than the somatic RAS pathway mutations assumed to be either the initiating event or part of the classical mechanism of leukemogenesis, such as hits targeting the wild-type NF1 or CBL allele in germline-mutated patients 8,9,48 . (a,b) The presence of any additional somatic alterations (a) together with RAS double mutations (b) allowed us to distinguish patients with a significantly poorer outcome.…”

mentioning

confidence: 98%

“…PDE8A, mutated in one PTPN11-JMML case, protects RAF1 from inhibitory phosphorylation by protein kinase A (PKA), enhancing its activity 11 . Two JMML cases with initiating lesions in NRAS (NRAS-JMML) had mutations in RRAS, an inducer of RAS-mitogen-activated protein kinase (MAPK) activation 12 and upstream regulator of RAC in hematopoietic stem cells 13 , and another had a mutation in the RHO GTPase RAC2. The coexistence of RAC and RAS-MAPK mutations in some tumors and cooperation between oncogenic NRAS and RAC has previously been demonstrated 14 .…”

mentioning

confidence: 99%

Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network

et al. 2015

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Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.

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“…CXCL12 treatment with and without NSC23766 in the FDCP-Mix cells enabled the data to be considered in the context of Rac inhibitor sensitive proteins. This is especially pertinent as Rac proteins are key effectors in p210-BCR-ABL mediated transformation (24) and stem cell homing/retention (1,3,24,38,39). The principal components of the experimental design are shown in Fig.…”

Section: Phosphoproteomic Analysis Of Cxcl12 Action On Multipotent Cementioning

confidence: 99%

A Specific PTPRC/CD45 Phosphorylation Event Governed by Stem Cell Chemokine CXCL12 Regulates Primitive Hematopoietic Cell Motility

Williamson

Pierce

Jaworska

et al. 2013

Molecular & Cellular Proteomics

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CXCL12 governs cellular motility, a process deregulated by hematopoietic stem cell oncogenes such as p210-BCR-ABL. A phosphoproteomics approach to the analysis of a hematopoietic progenitor cell line treated with CXCL12 and the Rac 1 and 2 inhibitor NSC23766 has been employed to objectively discover novel mechanisms for regulation of stem cells in normal and malignant hematopoiesis. The proteomic data sets identified new aspects of CXCL12-mediated signaling and novel features of stem cell regulation. We also identified a novel phosphorylation event in hematopoietic progenitor cells that correlated with motile response and governed by the chemotactic factor CXCL12. The novel phosphorylation site on PTPRC/ CD45; a protein tyrosine phosphatase, was validated by raising an antibody to the site and also using a mass spectrometry absolute quantification strategy. Site directed mutagenesis and inhibitor studies demonstrated that this single phosphorylation site governs hematopoietic progenitor cell and lymphoid cell motility, lies downstream from Rac proteins and potentiates Src signaling. We have also demonstrated that PTPRC/CD45 is downregulated in leukemogenic tyrosine kinase expressing cells. The use of discovery proteomics has enabled further understanding of the regulation of PTPRC/CD45 and its important role in cellular motility in progenitor cells. Molecular & Cellular

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R-Ras and Rac GTPase Cross-talk Regulates Hematopoietic Progenitor Cell Migration, Homing, and Mobilization

Cited by 17 publications

References 40 publications

An Increase in Tolerogenic Dendritic Cell and Natural Regulatory T Cell Numbers during Experimental Autoimmune Encephalomyelitis in Rras−/− Mice Results in Attenuated Disease

An Increase in Tolerogenic Dendritic Cell and Natural Regulatory T Cell Numbers during Experimental Autoimmune Encephalomyelitis in Rras−/− Mice Results in Attenuated Disease

Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network

A Specific PTPRC/CD45 Phosphorylation Event Governed by Stem Cell Chemokine CXCL12 Regulates Primitive Hematopoietic Cell Motility

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