Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency.

@article{Williams2000DominantNM,
  title={Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency.},
  author={D. A. Williams and Wen Tao and F C Yang and C N Kim and Y. Gu and Pamela J. Mansfield and Jason E. Levine and Bronislawa Petryniak and Caroline W. Derrow and Chad E. Harris and Baoqing Jia and Y. Zheng and Daniel R. Ambruso and John B. Lowe and Simon J. Atkinson and Mary C. Dinauer and Laurence A. Boxer},
  journal={Blood},
  year={2000},
  volume={96 5},
  pages={
          1646-54
        }
}
Rho GTPases control a variety of cellular processes, including actin polymerization, integrin complex formation, cell adhesion, gene transcription, cell cycle progression, and cell proliferation. A patient is described who has recurrent infections and defective neutrophil cellular functions similar to those found in Rac2-deficient mice. Molecular methods were used to clone the expressed Rac2 cDNA from this patient, and a single base pair change (G-->A at nucleotide 169) in the coding sequence… Expand
Biochemical and Biological Characterization of a Human Rac2 GTPase Mutant Associated with Phagocytic Immunodeficiency*
  • Yi Gu, B. Jia, +5 authors David A. Williams
  • Medicine, Biology
  • The Journal of Biological Chemistry
  • 2001
TLDR
The data suggest that the phenotypic abnormalities associated with D57N Rac2 may involve not only neutrophil cellular functions, but also abnormal cell survival in other hematopoietic cells and that overexpression of Rac leads to increased proliferation of normal cells in vitro, whereas deficiency of Rac leading to increased apoptosis. Expand
RAC2 GTPase deficiency and myeloid cell dysfunction in human and mouse.
TLDR
A critical and unique role for Rac2 in normal neutrophil function is demonstrated and a new genetic immunodeficiency syndrome in humans is defined and defined. Expand
A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic Protein 1 in lymphopoiesis and innate immunity
TLDR
It is demonstrated that Hem1 is essential for hematopoietic cell development, function, and homeostasis by controlling a distinct pathway leading to cytoskeletal reorganization, whereas NF-κB–dependent transcription proceeds independently of Hem1 and F-actin polymerization. Expand
Rac2D57N, a dominant inhibitory Rac2 mutant that inhibits p38 kinase signaling and prevents surface ruffling in bone-marrow-derived macrophages
TLDR
Examination of guanine nucleotide binding to recombinant Rac2D57N revealed reduced dissociation of GDP and association of GTP, which would inhibit Rac-dependent effects on actin cytoskeletal dynamics and p38 kinase signaling. Expand
Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects.
TLDR
This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates Rac2 from the related, ubiquitous RAC1. Expand
Human DOCK2 Deficiency: Report of a Novel Mutation and Evidence for Neutrophil Dysfunction
TLDR
A new kindred with four affected siblings harboring a homozygous splice-site mutation (c.2704-2 A > C) in DOCK2 is described, which affects EBV-B cell migration and results in NK cell dysfunction similar to previous observations. Expand
The TRQQKRP motif located near the C-terminus of Rac2 is essential for Rac2 biologic functions and intracellular localization.
TLDR
The results indicate that the TRQQKRP motif in Rac2protein is required for efficient prenylation and correct intracellular localization of Rac2 protein and is essential for Rac2 to mediate a variety of its biologic functions. Expand
RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells.
TLDR
The results suggest that RhoH serves as a negative regulator of both growth and actin-based function of HPCs possibly via suppression of Rac-mediated signaling. Expand
Rho GTPases in hematopoiesis and hemopathies.
TLDR
Mouse gene-targeting studies have provided convincing evidence that individual members of the Rho GTPase family are essential regulators of cell type-specific functions and stimuli-specific pathways in regulating hematopoietic stem cell interaction with bone marrow niche, erythropoiesis, and red blood cell actin dynamics, phagocyte migration and killing, and T- and B-cell maturation. Expand
Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells.
TLDR
An antagonistic role of RhoH is identified in regulation of cortical F-actin assembly and chemotaxis via suppressing Rac1 membrane targeting and activation in primary HPCs and it is demonstrated that the subcellular localization and inhibitory function of R HoH in H PCs are regulated by C-terminal motifs, including a CKIF prenylation site. Expand
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Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense.
TLDR
Rac2-deficient mice were created to define the physiological requirement for two near-identical Rac proteins in hematopoietic cells, and showed significant defects in chemotaxis, in shear-dependent L-selectin-mediated capture on the endothelial substrate Glycam-1, and in both F-actin generation and p38 and p42/p44 MAP kinase activation induced by chemoattractants. Expand
Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation.
  • D. Ambruso, C. Knall, +10 authors D. Roos
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 2000
TLDR
The description of an inhibitory mutation in a member of the Rho family of GTPases associated with a human immunodeficiency syndrome is described. Expand
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TLDR
Analysis of a panel of chimeras made between RhoA and Cdc42Hs, which all maintained the ability to respond to Dbl, their mutual GEF, and to GTPase-activating protein, revealed that at least two distinct sites in each of the GTPases are required for activation by the respective GEFs. Expand
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Specific pathways linking heterotrimeric G proteins and Fcγ receptors to the actin-based cytoskeleton are poorly understood. To test a requirement for Rho family members in cytoskeletal eventsExpand
An essential role for Rac in Ras transformation
TLDR
It is shown that Ratl fibroblasts expressing activated Val-12 Racl (Racl with valine at residue 12) display all the hallmarks of malignant transformation and that Rac is essential for transformation by Ras, indicating that oncogenic Ras drives both the Rac and MAP-kinase pathways, which cooperate to cause transformation. Expand
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TLDR
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TLDR
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TLDR
Rac 2 appears to be a third cytosolic component required for human neutrophil NADPH oxidase activation, and was found to possess the highest rate of intrinsic GTP hydrolysis of any of the characterized members of the Ras superfamily. Expand
Rho, Rac and Cdc42 regulate actin organization and cell adhesion in macrophages.
TLDR
It is concluded that in Bac1 macrophages Cdc42, Rac and Rho regulate the formation of distinct actin filament-based structures, and that CDC42 and Rac are also required for the assembly of adhesion sites to the extracellular matrix. Expand
Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation.
TLDR
Data support the possibility that oncogenic Ras activation of Rac1 and RhoA, coupled with activation of the Raf/MAPK pathway, is required to trigger the full morphogenic and mitogenic consequences of oncogen Ras transformation. Expand
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