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Review
. 2020 Sep 29:11:566192.
doi: 10.3389/fimmu.2020.566192. eCollection 2020.

Emerging Roles of Downstream of Kinase 3 in Cell Signaling

Jia Tong Loh  1   2 , Joey Kay Hui Teo  1   2 , Hong-Hwa Lim  1   3 , Kong-Peng Lam  1   2   4   5
Affiliations
Review

Emerging Roles of Downstream of Kinase 3 in Cell Signaling

Jia Tong Loh et al. Front Immunol. .

Abstract

Downstream of kinase (Dok) 3 is a member of the Dok family of adaptor proteins known to regulate signaling pathways downstream of various immunoreceptors. As Dok-3 lacks intrinsic catalytic activity, it functions primarily as a molecular scaffold to facilitate the nucleation of protein complexes in a regulated manner and hence, achieve specificity in directing signaling cascades. Since its discovery, considerable progress has been made toward defining the role of Dok-3 in limiting B cell-receptor signaling. Nonetheless, Dok-3 has since been implicated in the signaling of Toll-like and C-type lectin receptors. Emerging data further demonstrate that Dok-3 can act both as an activator and inhibitor, in lymphoid and non-lymphoid cell types, suggesting Dok-3 involvement in a plethora of signal transduction pathways. In this review, we will focus on the structure and expression profile of Dok-3 and highlight its role during signal transduction in B cells, innate cells as well as in bone and lung tissues.

Keywords: B cells; Dok-3; adaptor; cell signaling; innate cells.

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Figures

FIGURE 1
FIGURE 1
Schematic diagram of human Dok-3. Dok-3 has an amino-terminal pleckstrin homology (PH) and phosphotyrosine binding (PTB) domains, followed by a carboxy-terminal proline-rich region. Above, known phosphorylation, acetylation and methylation sites on Dok-3 mapped by mass spectrometry are indicated. Below, interaction partners of PH, PTB and proline-rich domains of Dok-3 are shown, together with their respective interacting domains/motifs/amino acid residues. The symbol “*” represents tyrosine residues on Dok-3 which bind specifically to SH2 domain of Grb2.
FIGURE 2
FIGURE 2
Overall domain architecture of Dok-1-7. (A) The Dok family proteins cluster into 3 subgroups, namely Dok-1/2/3, Dok-4/5/6 and Dok-7. All Dok proteins share an amino-terminal PH domain (blue) and a central PTB domain (pink). Dok-1 to -3 consist of a carboxy-terminal proline-rich region (green), Dok-4 to -6 a DKFBH motif (yellow), and Dok-7 a serine-rich region (gray). (B) The amino acid residues spanning each domain/motif and the total length of each Dok protein are indicated.
FIGURE 3
FIGURE 3
Summary of Dok-3 signaling pathways in B cell, macrophage, neutrophil and osteoclast precursor. Dok-3 functions downstream of multiple receptors including B-cell receptor (BCR), Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) to facilitate the nucleation of distinct signaling molecules and adapt them to regulate cellular functions in a spatially and temporally regulated manner. (A) Dok-3 limits BCR signaling by recruiting Grb2/SHIP1 to attenuate calcium flux, interacts with Csk to inhibit NFAT, or sequesters Abl to attenuate MAPK signaling. Dok-3 also associates with Grb2/Cbl to facilitate B cell spreading and transport of BCR microclusters for B cell activation to occur. (B) Dok-3 is phosphorylated upon low-dose or ubiquitinated and subsequently degraded upon high-dose LPS stimulation, thereby inhibiting TLR4 signaling in macrophages. Dok-3 also negatively regulates signaling downstream of TLR9. In contrast, Dok-3 is phosphorylated upon TLR3 activation leading to IRF3 induction and IFNβ production. (C) Dok-3 also participates in CLR signaling by recruiting PP1 to dephosphorylate Card9 for the attenuation of anti-fungal responses. (D) Dok-3 interacts with DAP12 to inhibit osteoclastogenesis.
FIGURE 4
FIGURE 4
Proposed model for small-molecule inhibition of Dok-3/Card9 binding. Dok-3 recruits Protein phosphatase 1 (PP1) to maintain Card9 in its de-phosphorylated and inactive state in neutrophils. A small-molecule inhibitor targeting hot spots on the Dok-3/Card9 binding interface disrupts interaction between Dok-3 and Card9, allowing Card9 to be phosphorylated and activated, thereby turning on downstream anti-fungal effector functions leading to fungal clearance.
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