HemITAM: A single tyrosine motif that packs a punch

Bauer, Björn; Steinle, Alexander

doi:10.1126/scisignal.aan3676

Cited by 23 publications

(26 citation statements)

References 99 publications

(172 reference statements)

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“…The results shown above indicate that the β-glucan structure is an important factor in signaling outcomes. Previous research has shown that other transmembrane CTLs that also contain a (hem)ITAM domain can form homodimers before or upon ligand recognition [56, 57]. Furthermore, crystallography studies of the carbohydrate recognition domain (CRD) have shown that Dectin-1A head groups form dimers when laminarin is present [58].…”

Section: Resultsmentioning

confidence: 99%

Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls

Anaya

Wester

et al. 2019

Preprint

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Candidemia is the most common bloodstream infection in the United States. During 23 infection, the fungal cell wall is an important virulence factor, playing roles in adhesion, 24 immune recognition and colonization. The human innate immune system recognizes β-25 glucan, a highly immunogenic component of the fungal cell wall. During innate immune 26 recognition of Candida, the organization of cell wall β-glucan is an important 27 determinant of a successful immune activation. However, there have been many reports 28 showing conflicting biological activities of β-glucans with different size, branching and 29 structure. Here, using quantitative fluorescence imaging techniques, we investigate how 30 differential size and structure of β-glucan impacts activation of the innate immune 31 receptor, Dectin-1A. Our results indicate a positive correlation between highly structured 32 glucans and Dectin-1A activation. Furthermore, we determined this is due to the higher 33 ordered β-glucan causing Dectin-1A receptors to form aggregates that are below 15 nm 34 in size. Finally, Dectin-1A receptor aggregation has also been shown to form at fungal 35 particle contact sites with high β-glucan exposure. 36 Abstract 37Dectin-1A is a C-type Lectin innate immunoreceptor that recognizes β-(1,3:1,6)-glucan, 38 a structural component of Candida species cell walls. The higher order structure of β-39 glucans ranges from random coil to insoluble fiber due to varying degrees of tertiary 40 (helical) and quaternary structure. Model Saccharomyces cerevisiae β-glucans of 41 medium and high molecular weight (MMW and HMW, respectively) are highly 42 structured. In contrast, low MW glucan (LMW) is much less structured. Despite similar 43 affinity for Dectin-1A, the ability of glucans to induce Dectin-1A mediated calcium influx 3 44and Syk phosphorylation positively correlates with their degree of higher order structure. 45Chemical denaturation and renaturation of MMW glucan showed that glucan structure 46 determines agonistic potential, but not binding affinity, for Dectin-1A. We explored the 47 6 113 ITAM domains poorly recruit and activate Syk for downstream signaling [44], suggesting 114 that hemITAM domains with their single phosphotyrosine site would be poorly activating 115 in a monomeric configuration. Consistent with this hypothesis, another (hem)ITAM 116 bearing receptor, CLEC-2, is reported to require dimerization for its signaling [45]. By 117 analogy to this and other (hem)ITAM receptors, it is hypothesized that Dectin-1A must 118 oligomerize to recapitulate a multivalent binding site for Syk and to facilitate signal 119 transduction [8,45,46]. However, this prediction has not been directly explored for 120Dectin-1A in live cells at the molecular level with relation to structural determinants of 121 receptor-ligand complex organization and signaling outcomes. 122In this study, we propose that factors that induce an aggregated membrane organization 123 of Dectin-1A during activation are very important for determining signaling ...

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Section: Resultsmentioning

confidence: 99%

Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls

Anaya

Wester

et al. 2019

Preprint

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“…Decreased Clec2 stability is consistent with a previous report demonstrating that tetraspanin CD37, the closest phylogenetic relative to CD82, is required for cell surface expression of a related family member, dectin-1 ( Meyer-Wentrup et al, 2007 ). Both Clec2 and dectin-1 contain hemITAM motifs that signal to Syk and Vav ( Bauer and Steinle, 2017 ). Whether Clec2 contributes to Syk and Vav signaling via integrin αvβ3 or whether it acts independently is unclear and warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Regulation of cytoskeleton and adhesion signaling in osteoclasts by tetraspanin CD82

et al. 2019

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We used a myeloid-specific Cre to conditionally delete CD82 in mouse osteoclasts and their precursors. In contrast to global loss of CD82 (gKO), conditional loss of CD82 (cKO) in osteoclasts does not affect cortical bone, osteoblasts, or adipocytes. CD82 loss results in greater trabecular volume and trabecular number but reduced trabecular space in 6-month old male mice. Though this trend is present in females it did not reach significance; whereas there was an increase in osteoclast numbers and eroded surface area only in female cKO mice. In vitro, there is an increase in osteoclast fusion and defects in actin assembly in both gKO and cKO mice, irrespective of sex. This is accompanied by altered osteoclast morphology and decreased release of CTX in vitro. Integrin αvβ3 expression is reduced, while integrin β1 is increased. Signaling to Src, Syk, and Vav are also compromised. We further discovered that expression of Clec2 and its ligand, Podoplanin, molecules that also signal to Syk and Vav, are increased in differentiated osteoclasts. Loss of CD82 reduces their expression. Thus, CD82 is required for correct assembly of the cytoskeleton and to limit osteoclast fusion, both needed for normal osteoclast function.

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“…Intracellularly, CLEC-2 contains a hemi ITAM (hemITAM) YxxL motif in its cytoplasmatic tail, which is similar to ITAM motifs comprising a YxxLx(6–12)YxxL sequence [ 145 , 146 ]. Upon CLEC-2 ligand binding or antibody-mediated dimerisation, Src phosphorylates hemITAM and SH2 domain-containing tyrosine kinase Syk which in turn conducts additional hemITAM motif phosphorylation and autophosphorylation [ 147 – 149 ].…”

Section: Involvement Of Platelet Itam and Hemi Itam Receptors In Cancmentioning

confidence: 99%

Role of platelets and platelet receptors in cancer metastasis

2018

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The interaction of tumor cells with platelets is a prerequisite for successful hematogenous metastatic dissemination. Upon tumor cell arrival in the blood, tumor cells immediately activate platelets to form a permissive microenvironment. Platelets protect tumor cells from shear forces and assault of NK cells, recruit myeloid cells by secretion of chemokines, and mediate an arrest of the tumor cell platelet embolus at the vascular wall. Subsequently, platelet-derived growth factors confer a mesenchymal-like phenotype to tumor cells and open the capillary endothelium to expedite extravasation in distant organs. Finally, platelet-secreted growth factors stimulate tumor cell proliferation to micrometastatic foci. This review provides a synopsis on the current literature on platelet-mediated effects in cancer metastasis and particularly focuses on platelet adhesion receptors and their role in metastasis. Immunoreceptor tyrosine-based activation motif (ITAM) and hemi ITAM (hemITAM) comprising receptors, especially, glycoprotein VI (GPVI), FcγRIIa, and C-type lectin-like-2 receptor (CLEC-2) are turned in the spotlight since several new mechanisms and contributions to metastasis have been attributed to this family of platelet receptors in the last years.

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HemITAM: A single tyrosine motif that packs a punch

Abstract: Certain genetically linked C-type lectin-like receptors that activate innate immune cells variably signal through their cytoplasmic hemITAM motifs.

Cited by 23 publications

References 99 publications

Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls

Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls

Regulation of cytoskeleton and adhesion signaling in osteoclasts by tetraspanin CD82

Role of platelets and platelet receptors in cancer metastasis

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