Spatial control of Draper receptor signaling initiates apoptotic cell engulfment

Williamson, Adam P; Vale, Ronald D.

doi:10.1083/jcb.201711175

Cited by 22 publications

(24 citation statements)

References 54 publications

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“…We recently used a similar system to reveal that PD‐1 strongly co‐localizes with CD28, but partially segregates from TCR in CD8 + cytotoxic T cells . Finally, SLB has been used to study the immunological synapse of various innate immune cells …”

Section: Reconstitution Of Extracellular Binding Interactionsmentioning

confidence: 99%

Understanding T cell signaling using membrane reconstitution

Hui

2019

Immunological Reviews

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T cells are central players of our immune system, as their functions range from killing tumorous and virus-infected cells to orchestrating the entire immune response.In order for T cells to divide and execute their functions, they must be activated by antigen-presenting cells (APCs) through a cell-cell junction. Extracellular interactions between receptors on T cells and their ligands on APCs trigger signaling cascades comprised of protein-protein interactions, enzymatic reactions, and spatial reorganization events, to either stimulate or repress T cell activation. Plasma membrane is the major platform for T cell signaling. Recruitment of cytosolic proteins to membranebound receptors is a common critical step in many signaling pathways. Membranes decrease the dimensionality of protein-protein interactions to enable weak yet biologically important interactions. Membrane resident proteins can phase separate into micro-islands that promote signaling by enriching or excluding signal regulators.Moreover, some membrane lipids can either mediate or regulate cell signaling by interacting with signaling proteins. While it is critical to investigate T cell signaling in a cellular environment, the large number of signaling pathways involved and potential crosstalk have made it difficult to obtain precise, quantitative information on T cell signaling. Reconstitution of purified proteins to model membranes provides a complementary avenue for T cell signaling research. Here, I review recent progress in studying T cell signaling using membrane reconstitution approaches. K E Y W O R D Sgeometry, membrane, reconstitution, signaling, T cell | 45 HUI phosphorylation of ITAMs (immunoreceptor tyrosine-based activation motifs) within the CD3 subunits, catalyzed primarily by the membrane-associated Src family kinase Lck (lymphocyte-specific protein tyrosine kinase). 2 Tyrosine-phosphorylated CD3 chains recruit and activate the kinase ZAP70 (zeta-chain-associated protein kinase 70), 3,4 which then phosphorylates the tyrosine-rich membrane adapter LAT (linker of activated T cells). 5 Phospho-LAT (pLAT) then recruits and organizes a number of enzymes and adapter proteins to trigger MAPK (mitogen-activated protein kinase) signaling and cytoskeleton rearrangement. 6,7 Nevertheless, outstanding questions remain for TCR signaling.

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Section: Reconstitution Of Extracellular Binding Interactionsmentioning

confidence: 99%

Understanding T cell signaling using membrane reconstitution

Hui

2019

Immunological Reviews

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“…Draper has also been shown to cluster into mobile puncta in Drosophila macrophage cell lines—a process that is proposed to drive its activation cycle akin to the mammalian T cell receptor. 20 In order to investigate whether this occurs in vivo , we expressed Draper-EGFP in macrophages and visualized its localization through live imaging ( Figure 3 C). Limited Draper puncta were observed under basal conditions within the cell body of migrating macrophages.…”

Section: Resultsmentioning

confidence: 99%

PTPN21/Pez Is a Novel and Evolutionarily Conserved Key Regulator of Inflammation In Vivo

et al. 2021

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Summary Drosophila provides a powerful model in which to study inflammation in vivo , and previous studies have revealed many of the key signaling events critical for recruitment of immune cells to tissue damage. In the fly, wounding stimulates the rapid production of hydrogen peroxide (H 2 O 2 ). 1 , 2 This then acts as an activation signal by triggering a signaling pathway within responding macrophages by directly activating the Src family kinase (SFK) Src42A, 3 which in turn phosphorylates the damage receptor Draper. Activated Draper then guides macrophages to the wound through the detection of an as-yet unidentified chemoattractant. 3 , 4 , 5 Similar H 2 O 2 -activated signaling pathways are also critical for leukocyte recruitment following wounding in larval zebrafish, 6 , 7 , 8 , 9 where H 2 O 2 activates the SFK Lyn to drive neutrophil chemotaxis. In this study, we combine proteomics, live imaging, and genetics in the fly to identify a novel regulator of inflammation in vivo ; the PTP-type phosphatase Pez. Pez is expressed in macrophages and is critical for their efficient migration to wounds. Pez functions within activated macrophages downstream of damage-induced H 2 O 2 and operates, via its band 4.1 ezrin, radixin, and moesin (FERM) domain, together with Src42A and Draper to ensure effective inflammatory cell recruitment to wounds. We show that this key role is conserved in vertebrates, because “crispant” zebrafish larvae of the Draper ortholog (MEGF10) or the Pez ortholog (PTPN21) exhibit a failure in leukocyte recruitment to wounds. This study demonstrates evolutionary conservation of inflammatory signaling and identifies MEGF10 and PTPN21 as potential therapeutic targets for the treatment of inflammatory disorders.

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“…Ligation of Draper to phosphatidylserine induces phosphorylation of the cytosolic signaling domain of Draper (8,28). Intriguingly, Draper recognizes a diverse array of additional ligands in other contexts including the proteins Pretaporter (29) and DmCaBP1 (30) and the bacterial surface molecule Lipoteichoic acid (31).…”

Section: Draper and A Proximal Writer-reader-eraser Module Initiate Ementioning

confidence: 99%

“…The Megf10/Draper/CED-1 receptors are composed of functionally separable extracellular ligation and intracellular signaling modules. The modularity of engulfment receptors enables phagocyte reprogramming, as replacement of the extracellular domain with a new recognition element directs phagocytes to identify and ingest new targets (6)(7)(8). The organization of engulfment signaling is also modular at the level of the receptor proximal signaling networks.…”

Section: Introductionmentioning

confidence: 99%

Modular Organization of Engulfment Receptors and Proximal Signaling Networks: Avenues to Reprogram Phagocytosis

et al. 2021

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Transmembrane protein engulfment receptors expressed on the surface of phagocytes engage ligands on apoptotic cells and debris to initiate a sequence of events culminating in material internalization and immunologically beneficial outcomes. Engulfment receptors are modular, comprised of functionally independent extracellular ligation domains and cytosolic signaling motifs. Cognate kinases, adaptors, and phosphatases regulate engulfment by controlling the degree of receptor activation in phagocyte plasma membranes, thus acting as receptor-proximal signaling modules. Here, we review recent efforts to reprogram phagocytes using modular synthetic receptors composed of antibody-based extracellular domains fused to engulfment receptor signaling domains. To aid the development of new phagocyte reprogramming methods, we then define the kinases, adaptors, and phosphatases that regulate a conserved family of engulfment receptors. Finally, we discuss current challenges and opportunities for the field.

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Spatial control of Draper receptor signaling initiates apoptotic cell engulfment

Cited by 22 publications

References 54 publications

Understanding T cell signaling using membrane reconstitution

Understanding T cell signaling using membrane reconstitution

PTPN21/Pez Is a Novel and Evolutionarily Conserved Key Regulator of Inflammation In Vivo

Modular Organization of Engulfment Receptors and Proximal Signaling Networks: Avenues to Reprogram Phagocytosis

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