A physical interaction between the adaptor proteins DOK3 and DAP12 is required to inhibit lipopolysaccharide signaling in macrophages.


:DNAX-activating protein of 12 kD (DAP12) is an immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor protein found in myeloid cells and natural killer cells, and it couples to various receptors that mediate either cellular activation or inhibition. DAP12 inhibits Toll-like receptor (TLR) signaling, such as that of TLR4 in response to its ligand lipopolysaccharide (LPS), as well as cytokine responses by coupling to TREM2 (triggering receptor expressed on myeloid cells 2) at the plasma membrane. Understanding the mechanisms that inhibit inflammatory responses in macrophages is important for the development of therapies to treat inflammatory diseases. We show that inhibition of LPS responses by DAP12 is mediated by the adaptor protein DOK3 (downstream of kinase 3). DOK3 physically associated with the ITAM of DAP12 through its phosphotyrosine-binding domain. In response to LPS, DOK3 was phosphorylated in a DAP12- and Src-dependent manner, which led to translocation of phosphorylated DOK3 to the plasma membrane. DOK3-deficient cells exhibited increased production of proinflammatory cytokines and activation of extracellular signal-regulated kinase (ERK). Compared to wild-type mice, DOK3-deficient mice had increased susceptibility to challenge with a sublethal dose of LPS and produced increased serum concentrations of the inflammatory cytokine tumor necrosis factor-α (TNF-α). Together, these data suggest the mechanism by which DAP12 and TREM2 inhibit LPS signaling in macrophages to prevent inflammation.


Sci Signal


Science signaling


Peng Q,Long CL,Malhotra S,Humphrey MB




Has Abstract


2013-08-20 00:00:00














  • New connections: New targets for fighting hepatic steatosis.

    abstract::Insight into the signaling pathways that regulate de novo lipogenesis may lead to new treatments for hepatic steatosis. ...

    journal_title:Science signaling

    pub_type: 杂志文章,评审


    authors: Wong W

    更新日期:2017-02-21 00:00:00

  • Transglutaminase-catalyzed protein-protein cross-linking suppresses the activity of the NF-κB-like transcription factor relish.

    abstract::Cross-linking of proteins by mammalian transglutaminases (TGs) plays important roles in physiological phenomena such as blood coagulation and skin formation. We show that Drosophila TG suppressed innate immune signaling in the gut. RNA interference (RNAi) directed against TG reduced the life span of flies reared under...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Shibata T,Sekihara S,Fujikawa T,Miyaji R,Maki K,Ishihara T,Koshiba T,Kawabata S

    更新日期:2013-07-23 00:00:00

  • Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes.

    abstract::Type 1 diabetes mellitus (T1DM) is associated with chronic systemic inflammation and enhanced susceptibility to systemic bacterial infection (sepsis). We hypothesized that low insulin concentrations in T1DM trigger the enzyme 5-lipoxygenase (5-LO) to produce the lipid mediator leukotriene B4 (LTB4), which triggers sys...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Filgueiras LR,Brandt SL,Wang S,Wang Z,Morris DL,Evans-Molina C,Mirmira RG,Jancar S,Serezani CH

    更新日期:2015-01-27 00:00:00

  • Metabotropic glutamate receptors and fragile x mental retardation protein: partners in translational regulation at the synapse.

    abstract::Fragile X syndrome (FXS) mental retardation is caused by loss-of-function mutations in an RNA-binding protein, fragile X mental retardation protein (FMRP). Previous studies in patients or animal models of FXS have identified alterations in dendritic spine structure, as well as synaptic plasticity induced by metabotrop...

    journal_title:Science signaling

    pub_type: 杂志文章,评审


    authors: Ronesi JA,Huber KM

    更新日期:2008-02-05 00:00:00

  • A direct screen for c-di-GMP modulators reveals a Salmonella Typhimurium periplasmic ʟ-arginine-sensing pathway.

    abstract::Cyclic-di-GMP (c-di-GMP) is a bacterial second messenger that transduces internal and external signals and regulates bacterial motility and biofilm formation. Some organisms encode more than 100 c-di-GMP-modulating enzymes, but only for a few has a signal been defined that modulates their activity. We developed and ap...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Mills E,Petersen E,Kulasekara BR,Miller SI

    更新日期:2015-06-09 00:00:00

  • 4-1BB costimulation promotes CAR T cell survival through noncanonical NF-κB signaling.

    abstract::Clinical response to chimeric antigen receptor (CAR) T cell therapy is correlated with CAR T cell persistence, especially for CAR T cells that target CD19+ hematologic malignancies. 4-1BB-costimulated CAR (BBζ) T cells exhibit longer persistence after adoptive transfer than do CD28-costimulated CAR (28ζ) T cells. 4-1B...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Philipson BI,O'Connor RS,May MJ,June CH,Albelda SM,Milone MC

    更新日期:2020-03-31 00:00:00

  • A nanoscale reorganization of the IL-15 receptor is triggered by NKG2D in a ligand-dependent manner.

    abstract::Natural killer group 2D (NKG2D), an activating receptor on natural killer (NK) cells and a subset of T cells, recognizes stress-inducible proteins, including MICA and ULBP2, which are present on infected or transformed cells. Whether each NKG2D ligand (NKG2DL) has a distinct biological role is not clear. Using superre...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Bálint Š,Lopes FB,Davis DM

    更新日期:2018-04-10 00:00:00

  • Cycles of ubiquitination and deubiquitination critically regulate growth factor-mediated activation of Akt signaling.

    abstract::K63-linked ubiquitination of Akt is a posttranslational modification that plays a critical role in growth factor-mediated membrane recruitment and activation of Akt. Although E3 ligases involved in growth factor-induced ubiquitination of Akt have been defined, the deubiquitinating enzyme (DUB) that triggers deubiquiti...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Yang WL,Jin G,Li CF,Jeong YS,Moten A,Xu D,Feng Z,Chen W,Cai Z,Darnay B,Gu W,Lin HK

    更新日期:2013-01-08 00:00:00

  • Drosophila toll pathway: the new model.

    abstract::In Drosophila, recognition of microbe-specific molecules (such as bacterial peptidoglycans) activates serine protease cascades that converge to activate the Toll pathway. Recent data show that the serine protease Grass, which is activated downstream of pattern recognition receptors and was initially thought to be a co...

    journal_title:Science signaling

    pub_type: 杂志文章,评审


    authors: Ashok Y

    更新日期:2009-01-06 00:00:00

  • Grooming and growing with microglia.

    abstract::Microglia mediate neuroprotection and neuropathogenesis but have not been directly associated with behavior. As gatekeepers of the brain's immune system, microglia protect the brain from pathogens but also contribute to inflammation, which may negatively affect neurons. A recent study demonstrates a role for Hoxb8-exp...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Antony JM

    更新日期:2010-11-09 00:00:00

  • Neuroligin-2 as a central organizer of inhibitory synapses in health and disease.

    abstract::Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of s...

    journal_title:Science signaling

    pub_type: 杂志文章,评审


    authors: Ali H,Marth L,Krueger-Burg D

    更新日期:2020-12-22 00:00:00

  • Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease.

    abstract::Alzheimer's disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-β (Aβ) accumulation in the brain. Through whole-genome sequencing of 1345 individuals from 410 families with late-onset AD (LOAD), we identified three highly penetrant variants in PRKCA, the gene that encodes...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Alfonso SI,Callender JA,Hooli B,Antal CE,Mullin K,Sherman MA,Lesné SE,Leitges M,Newton AC,Tanzi RE,Malinow R

    更新日期:2016-05-10 00:00:00

  • Prostaglandin E2-EP2-NF-κB signaling in macrophages as a potential therapeutic target for intracranial aneurysms.

    abstract::Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflamm...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Aoki T,Frȍsen J,Fukuda M,Bando K,Shioi G,Tsuji K,Ollikainen E,Nozaki K,Laakkonen J,Narumiya S

    更新日期:2017-02-07 00:00:00

  • Tuning the regulator: Phosphorylation of KCC2 at two specific sites is critical for neurodevelopment.

    abstract::The K+/Cl- cotransporter KCC2 is a molecular switch between excitatory and inhibitory effects of GABAergic inputs into neurons. In a pair of exciting studies, Watanabe et al. and Pisella et al. elucidate the role of KCC2 dephosphorylation in this process and reveal its consequences for neurodevelopment and nervous sys...

    journal_title:Science signaling

    pub_type: 评论,杂志文章,评审


    authors: Zamponi GW

    更新日期:2019-10-15 00:00:00

  • Itk controls the spatiotemporal organization of T cell activation.

    abstract::During T cell activation by antigen-presenting cells (APCs), the diverse spatiotemporal organization of components of T cell signaling pathways modulates the efficiency of activation. Here, we found that loss of the tyrosine kinase interleukin-2 (IL-2)-inducible T cell kinase (Itk) in mice altered the spatiotemporal d...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Singleton KL,Gosh M,Dandekar RD,Au-Yeung BB,Ksionda O,Tybulewicz VL,Altman A,Fowell DJ,Wülfing C

    更新日期:2011-10-04 00:00:00

  • An "inordinate fondness for transporters" explained?

    abstract::An often-asked question is, Why are there so many different transporters in a cell to take up a particular substrate? At least part of the answer comes from work on the possible competitive advantage of dual-transporter systems. In such systems, low-affinity transporters function when a nutrient is plentiful in the en...

    journal_title:Science signaling

    pub_type: 杂志文章,评审


    authors: Eide DJ

    更新日期:2012-02-07 00:00:00

  • A large bioactive BMP ligand with distinct signaling properties is produced by alternative proconvertase processing.

    abstract::Dimers of conventional transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) ligands are composed of two 100- to 140-amino acid peptides that are produced through the proteolytic processing of a proprotein precursor by proconvertases, such as furin. We report the identification of an evolutionarily...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Akiyama T,Marqués G,Wharton KA

    更新日期:2012-04-03 00:00:00

  • c-MYC suppresses BIN1 to release poly(ADP-ribose) polymerase 1: a mechanism by which cancer cells acquire cisplatin resistance.

    abstract::Cancer cells acquire resistance to DNA-damaging therapeutic agents, such as cisplatin, but the genetic mechanisms through which this occurs remain unclear. We show that the c-MYC oncoprotein increases cisplatin resistance by decreasing production of the c-MYC inhibitor BIN1 (bridging integrator 1). The sensitivity of ...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Pyndiah S,Tanida S,Ahmed KM,Cassimere EK,Choe C,Sakamuro D

    更新日期:2011-03-29 00:00:00

  • MNK2 inhibits eIF4G activation through a pathway involving serine-arginine-rich protein kinase in skeletal muscle.

    abstract::Skeletal muscle mass is regulated by activity, metabolism, and the availability of nutrients. During muscle atrophy, MNK2 expression increases. We found that MNK2 (mitogen-activated protein kinase-interacting kinase 2), but not MNK1, inhibited proteins involved in promoting protein synthesis, including eukaryotic tran...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Hu SI,Katz M,Chin S,Qi X,Cruz J,Ibebunjo C,Zhao S,Chen A,Glass DJ

    更新日期:2012-02-14 00:00:00

  • Activation of CaMKIV by soluble amyloid-β1-42 impedes trafficking of axonal vesicles and impairs activity-dependent synaptogenesis.

    abstract::The prefibrillar form of soluble amyloid-β (sAβ1-42) impairs synaptic function and is associated with the early phase of Alzheimer's disease (AD). We investigated how sAβ1-42 led to presynaptic defects using a quantum dot-based, single particle-tracking method to monitor synaptic vesicle (SV) trafficking along axons. ...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Park D,Na M,Kim JA,Lee U,Cho E,Jang M,Chang S

    更新日期:2017-07-11 00:00:00

  • Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2).

    abstract::Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of "HER2-negative" (not ERBB2 amplified) tumors but are rare in "HER2-positive" (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Cocco E,Javier Carmona F,Razavi P,Won HH,Cai Y,Rossi V,Chan C,Cownie J,Soong J,Toska E,Shifman SG,Sarotto I,Savas P,Wick MJ,Papadopoulos KP,Moriarty A,Cutler RE Jr,Avogadri-Connors F,Lalani AS,Bryce RP,Chandarlapa

    更新日期:2018-10-09 00:00:00

  • HIF takes it up a notch.

    abstract::Notch signaling is used to choose cell fates in many developmental contexts. New evidence shows that circulating blood cells in Drosophila, in the absence of Notch ligand provided by neighboring cells, activate Notch signaling through stabilization with the hypoxia-inducible factor-α (HIF-α) transcription factor. Alth...

    journal_title:Science signaling

    pub_type: 杂志文章,评审


    authors: Johnson EA

    更新日期:2011-07-12 00:00:00

  • Beta-adrenergic regulation of the L-type Ca2+ channel Ca(V)1.2 by PKA rekindles excitement.

    abstract::When we are frightened, our hearts beat more rapidly and forcefully so we can fight more intensely or run away faster. This fight-or-flight response is triggered by the release of norepinephrine from neurons of the sympathetic nervous system. Norepinephrine activates the classic β-adrenergic receptor-heterotrimeric G(...

    journal_title:Science signaling

    pub_type: 评论,杂志文章


    authors: Hell JW

    更新日期:2010-09-28 00:00:00

  • T cell receptor signals to NF-κB are transmitted by a cytosolic p62-Bcl10-Malt1-IKK signalosome.

    abstract::Antigen-mediated stimulation of the T cell receptor (TCR) triggers activation of nuclear factor κB (NF-κB), a key transcriptional regulator of T cell proliferation and effector cell differentiation. TCR signaling to NF-κB requires both the Carma1-Bcl10-Malt1 (CBM) complex and the inhibitor of κB (IκB) kinase (IKK) com...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Paul S,Traver MK,Kashyap AK,Washington MA,Latoche JR,Schaefer BC

    更新日期:2014-05-13 00:00:00

  • B cells prevent preterm labor.

    abstract::Premature labor and consequent neonatal mortality may be prevented by stimulating the expression of PIBF1 in uterine B cells. ...

    journal_title:Science signaling

    pub_type: 评论,杂志文章


    authors: Ferrarelli LK

    更新日期:2017-01-17 00:00:00

  • miR-221/222 targeting of trichorhinophalangeal 1 (TRPS1) promotes epithelial-to-mesenchymal transition in breast cancer.

    abstract::Compared with the luminal subtype, the basal-like subtype of breast cancer has an aggressive clinical behavior, but the reasons for this difference between the two subtypes are poorly understood. We identified microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs that decrease expr...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Stinson S,Lackner MR,Adai AT,Yu N,Kim HJ,O'Brien C,Spoerke J,Jhunjhunwala S,Boyd Z,Januario T,Newman RJ,Yue P,Bourgon R,Modrusan Z,Stern HM,Warming S,de Sauvage FJ,Amler L,Yeh RF,Dornan D

    更新日期:2011-08-09 00:00:00

  • IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.

    abstract::Obesity or a high-fat diet represses the endoribonuclease activity of inositol-requiring enzyme 1α (IRE1α), a transducer of the unfolded protein response (UPR) in cells under endoplasmic reticulum (ER) stress. An impaired UPR is associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD), which is c...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Wang JM,Qiu Y,Yang Z,Kim H,Qian Q,Sun Q,Zhang C,Yin L,Fang D,Back SH,Kaufman RJ,Yang L,Zhang K

    更新日期:2018-05-15 00:00:00

  • A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria.

    abstract::Prokaryotic cell wall biosynthesis is coordinated with cell growth and division, but the mechanisms regulating this dynamic process remain obscure. Here, we describe a phosphorylation-dependent regulatory complex that controls peptidoglycan (PG) biosynthesis in Mycobacterium tuberculosis. We found that PknB, a PG-resp...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Gee CL,Papavinasasundaram KG,Blair SR,Baer CE,Falick AM,King DS,Griffin JE,Venghatakrishnan H,Zukauskas A,Wei JR,Dhiman RK,Crick DC,Rubin EJ,Sassetti CM,Alber T

    更新日期:2012-01-24 00:00:00

  • Human regulatory T cells rapidly suppress T cell receptor-induced Ca(2+), NF-κB, and NFAT signaling in conventional T cells.

    abstract::CD4(+)CD25(hi)Foxp3(+) regulatory T cells (T(regs)) are critical mediators of self-tolerance, which is crucial for the prevention of autoimmune disease, but T(regs) can also inhibit antitumor immunity. T(regs) inhibit the proliferation of CD4(+)CD25(-) conventional T cells (T(cons)), as well as the ability of these ce...

    journal_title:Science signaling

    pub_type: 杂志文章


    authors: Schmidt A,Oberle N,Weiss EM,Vobis D,Frischbutter S,Baumgrass R,Falk CS,Haag M,Brügger B,Lin H,Mayr GW,Reichardt P,Gunzer M,Suri-Payer E,Krammer PH

    更新日期:2011-12-20 00:00:00

  • The cytoplasmic tail of MUC1: a very busy place.

    abstract::The role of mucin 1 (MUC1) in protecting epithelia from microbial infection, enzymatic digestion, and other irritants has been appreciated for some time. In addition, MUC1 serves as a barrier to embryo implantation. MUC1 is highly abundant in many tumors in which its role in barrier function may serve to protect cells...

    journal_title:Science signaling

    pub_type: 杂志文章,评审


    authors: Carson DD

    更新日期:2008-07-08 00:00:00