The Rac activator DOCK2 regulates natural killer cell–mediated cytotoxicity in mice through the lytic synapse formation

Sakai, Yusuke; Tanaka, Yoshihiko; Yanagihara, Toyoshi; Watanabe, Masayoshi; Duan, Xuefeng; Terasawa, Masao; Nishikimi, Akihiko; Sanematsu, Fumiyuki; Fukui, Yoshihiro

doi:10.1182/blood-2012-12-475897

Cited by 39 publications

(33 citation statements)

References 43 publications

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“…Altogether, these data demonstrate that DOCK2 serves an essential role in NK and NKT cell biology, consistent with similar observations in mice 17,18 .…”

Section: Resultssupporting

confidence: 90%

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

Dobbs¹,

et al. 2015

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Background Combined immunodeficiencies (CIDs) denote inborn errors of T-cell immunity with T cells present but quantitatively or functionally deficient. Impaired humoral immunity, either due to a primary B cell defect or secondary to the T-cell defect, is also frequent. Consequently, patients with CID display severe infections and/or autoimmunity. The specific molecular, cellular, and clinical features of many types of CID remain unknown. Methods We performed genetic and cellular immunological studies in five unrelated children who shared a history of early-onset invasive bacterial and viral infections, with lymphopenia and defective T-, B-, and NK-cell responses. Two patients died early in childhood, whereas the other three underwent allogeneic hematopoietic stem cell transplantation with normalization of T cell function and clinical improvement. Results We identified bi-allelic mutations in the Dedicator Of Cytokinesis 2 (DOCK2) gene in these five patients. RAC1 activation was impaired in T cells. Chemokine-induced migration and actin polymerization were defective in T, B, and NK cells. NK-cell degranulation was also affected. The production of interferon (IFN)-α and -λ by peripheral blood mononuclear cells (PBMCs) was diminished following virus infection. Moreover, in DOCK2-deficient fibroblasts, virus replication was increased and there was enhanced virus-induced cell death, which could be normalized by treatment with IFN-α2β or upon expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a Mendelian disorder with pleiotropic defects of hematopoietic and non-hematopoietic immunity. Children with clinical features of CID, especially in the presence of early-onset, invasive infections may have this condition.

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“…Altogether, these data demonstrate that DOCK2 serves an essential role in NK and NKT cell biology, consistent with similar observations in mice 17,18 .…”

Section: Resultssupporting

confidence: 90%

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

Dobbs¹,

et al. 2015

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“…Additionally, we found that fMLFinduced phosphorylations of ERK, Akt, and p38, which are closely associated with Rac activation in neutrophils (3,6,7), are severely impaired in DKO neutrophils. The importance of DOCK2 and DOCK5 could be extended to human neutrophils, because fMLF-induced Rac activation, chemotaxis, and ROS production were almost completely lost when human peripheral blood neutrophils were treated with CPYPP (25)(26)(27). Our results thus identify DOCK5 as a Rac GEF that acts additively with DOCK2 in the GPCR-mediated signaling pathway in humans and mice.…”

Section: Discussionmentioning

confidence: 64%

“…To examine whether the role of DOCK2 and DOCK5 could be extended to human neutrophils, we used CPYPP, a small-molecule inhibitor that binds to the DHR-2 domain of DOCK-A subfamily members and inhibits their Rac GEF activity (25)(26)(27). As expected, treatment of human peripheral blood neutrophils with CPYPP at 100 mM reduced fMLF-induced Rac2 activation to 22.5% of the vehicle (DMSO)-treated samples (Fig.…”

Section: A Small-molecule Inhibitor Of Dock2/dock5 Suppresses Human Nmentioning

confidence: 99%

“…The bound proteins and the total lysate control (5 mg for Rac1 and 2 mg for Rac2) were analyzed by SDS-PAGE, and blots were probed with anti-Rac1 (23A8, Millipore) and anti-Rac2 (3B10-2D9, Sigma-Aldrich) Abs. In some experiments, human peripheral blood neutrophils were treated with CPYPP (100 mM), a small-molecule inhibitor of DOCK-A subfamily members (25)(26)(27), for 60 min before stimulation with fMLF (10 mM).…”

Section: Rac Activation Assaysmentioning

confidence: 99%

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DOCK2 and DOCK5 Act Additively in Neutrophils To Regulate Chemotaxis, Superoxide Production, and Extracellular Trap Formation

Watanabe

Terasawa

Miyano

et al. 2014

The Journal of Immunology

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Neutrophils are highly motile leukocytes that play important roles in the innate immune response to invading pathogens. Neutrophils rapidly migrate to the site of infections and kill pathogens by producing reactive oxygen species (ROS). Neutrophil chemotaxis and ROS production require activation of Rac small GTPase. DOCK2, an atypical guanine nucleotide exchange factor (GEF), is one of the major regulators of Rac in neutrophils. However, because DOCK2 deficiency does not completely abolish fMLF-induced Rac activation, other Rac GEFs may also participate in this process. In this study, we show that DOCK5 acts with DOCK2 in neutrophils to regulate multiple cellular functions. We found that fMLF- and PMA-induced Rac activation were almost completely lost in mouse neutrophils lacking both DOCK2 and DOCK5. Although β2 integrin–mediated adhesion occurred normally even in the absence of DOCK2 and DOCK5, mouse neutrophils lacking DOCK2 and DOCK5 exhibited a severe defect in chemotaxis and ROS production. Similar results were obtained when human neutrophils were treated with CPYPP, a small-molecule inhibitor of these DOCK GEFs. Additionally, we found that DOCK2 and DOCK5 regulate formation of neutrophil extracellular traps (NETs). Because NETs are involved in vascular inflammation and autoimmune responses, DOCK2 and DOCK5 would be a therapeutic target for controlling NET-mediated inflammatory disorders.

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“…2). A recent study from Fukui and colleagues demonstrated that PIP 3 also recruits Dock2 to the NK cell IS[83], suggesting that this pathway is conserved among all lymphocytes.…”

Section: Synaptic Actin Remodelingmentioning

confidence: 99%

Molecular mechanisms and functional implications of polarized actin remodeling at the T cell immunological synapse

Floc’h

Huse

2014

Cell. Mol. Life Sci.

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Transient, specialized cell-cell interactions play a central role in leukocyte function by enabling specific intercellular communication in the context of a highly dynamic systems level response. The dramatic structural changes required for the formation of these contacts are driven by rapid and precise cytoskeletal remodeling events. In recent years, the immunological synapse that forms between a T lymphocyte and its antigen-presenting target cell has emerged as an important model system for understanding immune cell interactions. In this review, we discuss how regulators of the cortical actin cytoskeleton control synaptic architecture and in this way specify T cell function.

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The Rac activator DOCK2 regulates natural killer cell–mediated cytotoxicity in mice through the lytic synapse formation

Cited by 39 publications

References 43 publications

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

DOCK2 and DOCK5 Act Additively in Neutrophils To Regulate Chemotaxis, Superoxide Production, and Extracellular Trap Formation

Molecular mechanisms and functional implications of polarized actin remodeling at the T cell immunological synapse

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