Dok-1 and Dok-2 are negative regulators of T cell receptor signaling

Yasuda, Tomoharu; Bundo, Kenji; Hino, Ayako; Honda, Kazuho; Inoue, Akane; Shirakata, Masaki; Osawa, Mitsujiro; Tamura, Toshiki; Nariuchi, Hideo; Oda, Hideaki; Yamamoto, Tadashi; Yamanashi, Yuji

doi:10.1093/intimm/dxm015

Cited by 80 publications

(83 citation statements)

References 33 publications

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“…The effect of Dok on thymic positive selection might become visible in TCR transgenic mouse model with low affinity ligand where selecting selfpeptides would be limited. In support of a role of Dok in positive selection, and in agreement with previous reports [16,25], we found that there is an increase in the absolute number of mature SP thymocytes in Dok-1-/Dok-2-deficient mice compared to WT mice (data not shown). Although other possibilities such as alteration of export of mature thymocytes to the periphery cannot be excluded, one possible explanation of these data is that in absence of Dok, positive selection of thymocytes is more efficient.…”

Section: Discussionsupporting

confidence: 93%

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Dok‐1 overexpression promotes development of γδ natural killer T cells

et al. 2012

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In T cells, two members of the Dok family, Dok-1 and Dok-2, are predominantly expressed. Recent evidence suggests that they play a negative role in T-cell signaling. In order to define whether Dok proteins regulate T-cell development, we have generated transgenic mice overexpressing Dok-1 in thymocytes and peripheral T cells. We show that overexpression of Dok-1 retards the transition from the CD4 − CD8 − to CD4 + CD8 + stage. Moreover, there is a specific expansion of PLZF-expressing Vγ1.1 + Vδ6.3 + T cells. This subset of γδ T cells acquires innate characteristics including rapid IL-4 production following stimulation and requiring SLAM-associated adaptor protein (SAP) for their development. Moreover, Dok-1 overexpression promotes the generation of an innate-like CD8 + T-cell population that expresses Eomesodermin. Altogether, these findings identify a novel role for Dok-1 in the regulation of thymic differentiation and in particular, in the development of PLZF + γδ T cells.Keywords: γδ T cell r Dok r PLZF r SAP r Thymocyte development Supporting Information available online Introduction αβ T-lymphocyte development is dependent on productive rearrangement of the TCRβ locus and intracellular signaling initiated through the pre-TCR at the CD4 − CD8 − double-negative (DN) stage. Pre-TCR signaling leads to cellular proliferation and progression to the CD4 + CD8 + double-positive (DP) stage where TCRα locus rearrangement is induced. In DP thymocytes, initial TCR signal strength/duration will determine specific gene expression and Correspondence: Dr. Pascale Duplay e-mail: pascale.duplay@iaf.inrs.ca as a consequence will regulate the outcome of thymocyte positive versus negative selection and CD4 versus CD8 lineage differentiation or conventional versus innate lymphocyte lineage choice [1].γδ TCR lymphocytes also develop in the thymus and require productive rearrangement of the TCRγ and δ loci at the DN stage. The strength of TCR signaling is important in controlling αβ/γδ lineage choice. Strong TCR signaling is required for the commitment to the γδ lineage whereas weak TCR signals favor * These authors contributed equally to this work. Eur. J. Immunol. 2012Immunol. . 42: 2491Immunol. -2504 development of αβ lineage cells (reviewed in [2][3][4]). Moreover, TCR signal strength regulates also maturation and acquisition of effector functions in γδ and αβ T-cell development. Therefore, signaling molecules that modulate TCR signal strength play a pivotal role in the regulation of T-cell development and homeostasis. Development signals from the pre-TCR and from the TCR are controlled by the coordinated activity of tyrosine kinases such as Syk-family kinases [5], Src-family kinases [6], and Tec-family kinases [7,8] and adaptor molecules such as , LAT [10], Grb2 [11], and Gads [12].Dok are adaptor proteins that contain a pleckstrin homology domain, a phosphotyrosine binding domain, and a COOHterminal region containing multiple tyrosine phosphorylation sites [13,14]. Dok-1 and Dok-2, the two members of Dok family proteins e...

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Section: Discussionsupporting

confidence: 93%

“…In Dok-1-and Dok-2-deficient mature T cells, phosphorylation of ZAP-70, LAT, SLP-76, Akt, and Erk1/2 is increased compared to wild-type (WT) cells [25,26] [33][34][35], and γδ/αβ lineage choice [36]. Given that TCR-mediated activation of Erk is inhibited by Dok, Dok might play an important role in thymocyte development.…”

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Dok‐1 overexpression promotes development of γδ natural killer T cells

et al. 2012

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“…Ample evidence indicates that they function as negative regulators of antigen receptor-and growth factor receptor-mediated cell proliferation and/or survival and that they act by interfering with the activation of distinct signaling pathways downstream of these receptors (31,33,39,53,61,82,86,90,94,95,98). In particular, upon tyrosine phosphorylation elicited by receptor stimulation, the Dok proteins dock to the plasma membrane in a PH domain-dependent manner, where they recruit inhibitory effector molecules via interactions involving their phosphorylated tyrosine residues and PxxP motifs and the SH2 and SH3 domains of the interacting partners, respectively (31,53,81,94,99). Through their ability to coordinate the formation of these signaling complexes, Dok-1, -2, and -3 establish negative feedback loops that antagonize receptor-initiated signaling pathways (33,39,53,86,90,98,99).…”

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Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Janas

Aelst

2011

Molecular and Cellular Biology

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Cellular transformation induced by oncogenic tyrosine kinases is a multistep process involving activation of growth-promoting signaling pathways and inactivation of suppressor molecules. Dok-1 is an adaptor protein that acts as a negative regulator of tyrosine kinase-initiated signaling and opposes oncogenic tyrosine kinasemediated cell transformation. Findings that its loss facilitates transformation induced by oncogenic tyrosine kinases suggest that Dok-1 inactivation could constitute an intermediate step in oncogenesis driven by these oncoproteins. However, whether Dok-1 is subject to regulation by oncogenic tyrosine kinases remained unknown. In this study, we show that oncogenic tyrosine kinases, including p210 bcr-abl and oncogenic forms of Src, downregulate Dok-1 by targeting it for degradation through the ubiquitin-proteasome pathway. This process is dependent on the tyrosine kinase activity of the oncoproteins and is mediated primarily by lysine-dependent polyubiquitination of Dok-1. Importantly, restoration of Dok-1 levels strongly suppresses transformation of cells expressing oncogenic tyrosine kinases, and this suppression is more pronounced in the context of a Dok-1 mutant that is largely refractory to oncogenic tyrosine kinase-induced degradation. Our findings suggest that proteasome-mediated downregulation of Dok-1 is a key mechanism by which oncogenic tyrosine kinases overcome the inhibitory effect of Dok-1 on cellular transformation and tumor progression.Protein tyrosine kinases (PTKs), of which more than 90 are encoded by the human genome, are key regulators of intracellular signal transduction pathways that control a variety of cellular processes, such as proliferation, differentiation, survival, cell movement, and cytoskeletal organization (46,52). Under physiological conditions, the activity of these kinases, including receptor and cytoplasmic PTKs, is tightly controlled to maintain cell and tissue homeostasis. However, when deregulated, due to, for example, mutations, gene amplifications, or impaired deactivation of the PTK, this control is lost, leading to aberrant downstream signaling, which can result in malignant transformation. To date, deregulation of more than 50 human PTKs has been implicated in the pathogenesis of various solid tumors and hematologic malignancies (2, 7, 36).Significant progress has been made toward unraveling the mechanisms of oncogenic activation of PTKs. Also, numerous studies have identified key signaling molecules and pathways that are activated by oncogenic tyrosine kinases (OTKs) and participate in mediating their effects on malignant transformation (45,55,57,71,72,75). However, besides triggering positive signaling events, OTKs also need to overcome negative regulatory constraints to drive tumor initiation and/or progression (7,24,42,57). These include, for instance, constraints brought about by tumor suppressors or inhibitory molecules that counteract the signaling activity triggered by the OTKs (17, 69). The nature of these "negative regulators" and, import...

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“…3,4,[10][11][12][13][14] Among these members, only Dok-1, Dok-2, and Dok-3 are preferentially expressed in hematopoietic cells, or myeloid cells in particular, and comprise a closely related subgroup with regard to primary structure. 7,9,15 Similar to Dok-1 and Dok-2, Dok-3 is also a negative regulator of PTKmediated signaling, despite being a relatively distant member of this subgroup. 11,[16][17][18][19] However, mice lacking Dok-3 alone or Dok-1 and its closest homolog Dok-2 in combination do not develop aggressive tumors of hematopoietic cells.…”

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Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma

Mashima

Honda

Yang

et al. 2010

Laboratory Investigation

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Histiocytic sarcoma (HS), a rare hematological malignancy, is an aggressive neoplasm that responds poorly to therapy. The molecular etiology and pathology of this disease remain unclear, hampering the development of an effective therapy, and there remains a need for more, and more realistic, animal models. HS cells typically show a histiocytic (ie, tissue macrophage-like) morphology and express histiocyte/macrophage markers in the absence of lymphocyte markers. In this study, we report that Dok-1 À/À Dok-2 À/À Dok-3 À/À mice develop HS, but do not exhibit elevated incidence of other types of tumors. These mutant mice showed earlier mortality than wild-type (WT) or the other mutant mice, and this mortality was associated with HS. In total, 17 of 21 tumor-bearing Dok-1À/À Dok-3 À/À mice necropsied at 25-66 weeks of age showed multiple organ spread, with osteolytic lesions and orthotopic invasion from the bone marrow to skeletal muscle. Tumors from the mice were transplantable. In addition, all Dok-1À/À Dok-3 À/À mice, but only a small proportion of Dok-3 À/À mice and no Dok-1 À/À Dok-2 À/À mice, exhibited abnormal accumulation of macrophages in the lung on necropsy at 8-12 weeks of age. Macrophages derived from Dok-1 À/À Dok-2 À/À Dok-3 À/À mice displayed an exaggerated proliferative response to macrophage colony-stimulating factor (M-CSF) or granulocytemacrophage colony-stimulating factor (GM-CSF) compared with WT and mutant controls. Together, these findings indicate that Dok-1, Dok-2, and Dok-3 cooperatively suppress aggressive HS, and commend Dok-1 À/À Dok-2 À/À Dok-3 À/À mice as a useful model for the study of this neoplasia.

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Dok-1 and Dok-2 are negative regulators of T cell receptor signaling

Cited by 80 publications

References 33 publications

Dok‐1 overexpression promotes development of γδ natural killer T cells

Dok‐1 overexpression promotes development of γδ natural killer T cells

Oncogenic Tyrosine Kinases Target Dok-1 for Ubiquitin-Mediated Proteasomal Degradation To Promote Cell Transformation

Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma

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