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author:("Yan, jianshi")
1.  Arrestins function in cAR1 GPCR-mediated signaling and cAR1 internalization in the development of Dictyostelium discoideum 
Molecular Biology of the Cell  2014;25(20):3210-3221.
Evolutionarily conserved arrestin-like proteins are key components of the cAR1-mediated ERK2 activation that controls cAMP cell–cell signaling during Dictyostelium aggregation. They are also involved in ligand-induced cAR1 internalization, which is required for the switch of cAMP receptors during multicellular development.
Oscillation of chemical signals is a common biological phenomenon, but its regulation is poorly understood. At the aggregation stage of Dictyostelium discoideum development, the chemoattractant cAMP is synthesized and released at 6-min intervals, directing cell migration. Although the G protein–coupled cAMP receptor cAR1 and ERK2 are both implicated in regulating the oscillation, the signaling circuit remains unknown. Here we report that D. discoideum arrestins regulate the frequency of cAMP oscillation and may link cAR1 signaling to oscillatory ERK2 activity. Cells lacking arrestins (adcB−C−) display cAMP oscillations during the aggregation stage that are twice as frequent as for wild- type cells. The adcB−C− cells also have a shorter period of transient ERK2 activity and precociously reactivate ERK2 in response to cAMP stimulation. We show that arrestin domain–containing protein C (AdcC) associates with ERK2 and that activation of cAR1 promotes the transient membrane recruitment of AdcC and interaction with cAR1, indicating that arrestins function in cAR1-controlled periodic ERK2 activation and oscillatory cAMP signaling in the aggregation stage of D. discoideum development. In addition, ligand-induced cAR1 internalization is compromised in adcB−C− cells, suggesting that arrestins are involved in elimination of high-affinity cAR1 receptors from cell surface after the aggregation stage of multicellular development.
PMCID: PMC4196870  PMID: 25143405
2.  Signaling network from GPCR to the actin cytoskeleton during chemotaxis 
Bioarchitecture  2012;2(1):15-18.
Chemotaxis is crucial for many physiological processes including the recruitment of leukocytes to sites of infection, trafficking of lymphocytes in the human body, and metastasis of cancer cells. A family of small proteins, chemokines, serves as the signals, and a family of G-protein coupled receptors (GPCRs) detects chemokines and direct cell migration. One of the basic questions in chemotaxis of eukaryotes is how a GPCR transduces signals to control the assembly of the actin network that generates directional force for cell migration. Over the past decade, a variety of signaling components have been implicated to transduce the GPCR signaling to the actin cytoskeleton. Studies in a lower eukaryotic organism, Dictyostelium discoideum, have allowed us to discover evolutionary conversed components involved in the GPCR-controlled actin network during chemotaxis. However, complete pathways linking GPCR to the actin network are still far from clear. Here we first summarize the previous studies on these components, and then update with our finding showing a new pathway, consisting of a GPCR, Gβγ, Elmo/Dock, Rac and Arp2/3 and actin. We suggest that this pathway serves as a direct linkage between the GPCR/G-protein, the chemoattractant sensing machinery, and the actin cytoskeleton, the machinery of cell movement during chemotaxis of eukaryotic cells.
PMCID: PMC3383712  PMID: 22754623
Dictyostelium; Dock; Elmo; GPCR; actin; chemotaxis; cytoskeleton; signaling
3.  The Elmo family forms an ancient group of actin-regulating proteins 
The Elmo protein family members are important mediators of small G protein activity, regulating actin-mediated processes such as chemotaxis and engulfment. Until recently,1 Elmo function has not been explored in professional phagocytes such as Dictyostelium discoideum. We discuss the significance of this family with respect to pathways that regulate Rac signaling, we present a comparison of Elmo proteins between representative taxa, and discuss our findings on ElmoA, one of six Elmo proteins found in D. discoideum.
PMCID: PMC2734041  PMID: 19721884
Elmo; TIRFM; Dictyostelium; actin; myosin; small G-protein; chemotaxis
4.  Locally controlled inhibitory mechanisms are involved in eukaryotic GPCR-mediated chemosensing 
The Journal of Cell Biology  2007;178(1):141-153.
Gprotein–coupled receptor (GPCR) signaling mediates a balance of excitatory and inhibitory activities that regulate Dictyostelium chemosensing to cAMP. The molecular nature and kinetics of these inhibitors are unknown. We report that transient cAMP stimulations induce PIP3 responses without a refractory period, suggesting that GPCR-mediated inhibition accumulates and decays slowly. Moreover, exposure to cAMP gradients leads to asymmetric distribution of the inhibitory components. The gradients induce a stable accumulation of the PIP3 reporter PHCrac-GFP in the front of cells near the cAMP source. Rapid withdrawal of the gradient led to the reassociation of G protein subunits, and the return of the PIP3 phosphatase PTEN and PHCrac-GFP to their pre-stimulus distribution. Reapplication of cAMP stimulation produces a clear PHCrac-GFP translocation to the back but not to the front, indicating that a stronger inhibition is maintained in the front of a polarized cell. Our study demonstrates a novel spatiotemporal feature of currently unknown inhibitory mechanisms acting locally on the PI3K activation pathway.
PMCID: PMC2064430  PMID: 17606871
5.  Association between Gαi2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis 
Nature Communications  2013;4:1706-.
The chemokine CXCL12 and its G-protein-coupled receptor CXCR4 control the migration, invasiveness and metastasis of breast cancer cells. Binding of CXCL12 to CXCR4 triggers activation of heterotrimeric Gi proteins that regulate actin polymerization and migration. However, the pathways linking chemokine G-protein-coupled receptor/Gi signalling to actin polymerization and cancer cell migration are not known. Here we show that CXCL12 stimulation promotes interaction between Gαi2 and ELMO1. Gi signalling and ELMO1 are both required for CXCL12-mediated actin polymerization, migration and invasion of breast cancer cells. CXCL12 triggers a Gαi2-dependent membrane translocation of ELMO1, which associates with Dock180 to activate small G-proteins Rac1 and Rac2. In vivo, ELMO1 expression is associated with lymph node and distant metastasis, and knocking down ELMO1 impairs metastasis to the lung. Our findings indicate that a chemokine-controlled pathway, consisting of Gαi2, ELMO1/Dock180, Rac1 and Rac2, regulates the actin cytoskeleton during breast cancer metastasis.
Chemokines promote breast cancer metastasis by stimulating re-organization of the actin cytoskeleton. Li et al. identify the human engulfment and cell motility protein ELMO1 as an intermediary between chemokine-dependent Gαi2 signalling and small GTPase signalling mediated by Rac.
PMCID: PMC3644068  PMID: 23591873

Results 1-5 (5)