Dedicator of Cytokinesis 2 in Cell Signaling Regulation and Disease Development

Guo, Xia; Chen, Shiyou

doi:10.1002/jcp.25512

Cited by 26 publications

(18 citation statements)

References 143 publications

(236 reference statements)

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Section: Introductionmentioning

confidence: 99%

“…Among DOCK proteins, DOCK2 plays multiple roles in regulating immune responses 32 . It is a haematopoietic cell protein which functions downstream of chemokine receptors to control actin reorganization, thus, regulating lymphocyte activation, migration, and morphology 32 , 33 . In T cells DOCK2 acts downstream of the T cell receptor, and recently DOCK2 was implicated in mediating signalling from the FLT3 protein tyrosine kinase and identified as a leukaemia drug target 32 , 33 .…”

Section: Introductionmentioning

confidence: 99%

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Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state

Chang

Yang

et al. 2020

Nat Commun

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DOCK (dedicator of cytokinesis) proteins are multidomain guanine nucleotide exchange factors (GEFs) for RHO GTPases that regulate intracellular actin dynamics. DOCK proteins share catalytic (DOCK DHR2 ) and membrane-associated (DOCK DHR1 ) domains. The structurally-related DOCK1 and DOCK2 GEFs are specific for RAC, and require ELMO (engulfment and cell motility) proteins for function. The N-terminal RAS-binding domain (RBD) of ELMO (ELMO RBD ) interacts with RHOG to modulate DOCK1/2 activity. Here, we determine the cryo-EM structures of DOCK2−ELMO1 alone, and as a ternary complex with RAC1, together with the crystal structure of a RHOG−ELMO2 RBD complex. The binary DOCK2−ELMO1 complex adopts a closed, auto-inhibited conformation. Relief of auto-inhibition to an active, open state, due to a conformational change of the ELMO1 subunit, exposes binding sites for RAC1 on DOCK2 DHR2 , and RHOG and BAI GPCRs on ELMO1. Our structure explains how up-stream effectors, including DOCK2 and ELMO1 phosphorylation, destabilise the auto-inhibited state to promote an active GEF.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state

Chang

Yang

et al. 2020

Nat Commun

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“…The increased inflammation in adipose tissue and low-grade system inflammation appear to be important (28). DOCK2 regulates lymphocyte activation and various immunological functions indicating a vital role in regulating inflammation (16). Indeed, the attenuation of diet-induced obesity Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Dedicator of cytokinesis 2 (DOCK2) is an atypical guanine nucleotide exchange factor (GEF) for the Rho-small guanine triphosphatase mainly expressed in hematopoietic cells that regulates lymphocyte activation and migration (15). DOCK2 also controls various immunological functions including helper T cell differentiation, neutrophil chemotaxis, and type I interferon induction (16). Recently, we found that DOCK2 modulates SMC phenotype by inhibiting myocardin-mediated SMC gene transcription (17).…”

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confidence: 99%

DOCK2 deficiency mitigates HFD-induced obesity by reducing adipose tissue inflammation and increasing energy expenditure

Guo

et al. 2017

Journal of Lipid Research

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Obesity is the major risk factor for type 2 diabetes, cardiovascular disorders, and many other diseases. Adipose tissue inflammation is frequently associated with obesity and contributes to the morbidity and mortality. Dedicator of cytokinesis 2 (DOCK2) is involved in several inflammatory diseases, but its role in obesity remains unknown. To explore the function of DOCK2 in obesity and insulin resistance, WT and DOCK2-deficient (DOCK2) mice were given chow or high-fat diet (HFD) for 12 weeks followed by metabolic, biochemical, and histologic analyses. DOCK2 was robustly induced in adipose tissues of WT mice given HFD. DOCK2 mice with HFD showed decreased body weight gain and improved metabolic homeostasis and insulin resistance compared with WT mice. DOCK2 deficiency also attenuated adipose tissue and systemic inflammation accompanied by reduced macrophage infiltration. Moreover, DOCK2 mice exhibited increased expression of metabolic genes in adipose tissues with greater energy expenditure. Mechanistically, DOCK2 appeared to regulate brown adipocyte differentiation because increased preadipocyte differentiation to brown adipocytes in interscapular and inguinal fat was observed in DOCK2 mice, as compared with WT. These data indicated that DOCK2 deficiency protects mice from HFD-induced obesity, at least in part, by stimulating brown adipocyte differentiation. Therefore, targeting DOCK2 may be a potential therapeutic strategy for treating obesity-associated diseases.

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“…Herein, we observed that the highest number of ligand peptides reported were for SH3, WW and PDZ domains. Proteins containing these domains were known to play crucial roles in critical diseases like cancer and neurodegenerative disorders [ 18 – 23 ], and hence, peptides binding to these three domains were extensively studied. Although prediction servers have been previously developed for SH3, WW and PDZ binding peptides, we selected SH3, WW and PDZ domains for developing better prediction methods for domain-specific peptide interactions.…”

Section: Introductionmentioning

confidence: 99%

LMDIPred: A web-server for prediction of linear peptide sequences binding to SH3, WW and PDZ domains

2018

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Protein-peptide interactions form an important subset of the total protein interaction network in the cell and play key roles in signaling and regulatory networks, and in major biological processes like cellular localization, protein degradation, and immune response. In this work, we have described the LMDIPred web server, an online resource for generalized prediction of linear peptide sequences that may bind to three most prevalent and well-studied peptide recognition modules (PRMs)—SH3, WW and PDZ. We have developed support vector machine (SVM)-based prediction models that achieved maximum Matthews Correlation Coefficient (MCC) of 0.85 with an accuracy of 94.55% for SH3, MCC of 0.90 with an accuracy of 95.82% for WW, and MCC of 0.83 with an accuracy of 92.29% for PDZ binding peptides. LMDIPred output combines predictions from these SVM models with predictions using Position-Specific Scoring Matrices (PSSMs) and string-matching methods using known domain-binding motif instances and regular expressions. All of these methods were evaluated using a five-fold cross-validation technique on both balanced and unbalanced datasets, and also validated on independent datasets. LMDIPred aims to provide a preliminary bioinformatics platform for sequence-based prediction of probable binding sites for SH3, WW or PDZ domains.

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Dedicator of Cytokinesis 2 in Cell Signaling Regulation and Disease Development

Cited by 26 publications

References 143 publications

Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state

Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state

DOCK2 deficiency mitigates HFD-induced obesity by reducing adipose tissue inflammation and increasing energy expenditure

LMDIPred: A web-server for prediction of linear peptide sequences binding to SH3, WW and PDZ domains

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