Transmembrane chemokines act as receptors in a novel mechanism termed inverse signaling

Hattermann, Kirsten; Gebhardt, Holger; Krossa, Sebastian; Ludwig, Andreas; Lucius, Ralph; Held‐Feindt, Janka; Mentlein, Rolf

doi:10.7554/elife.10820

Cited by 23 publications

(46 citation statements)

References 49 publications

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“…Additionally, in accordance with our recent findings in gliomas [10], application of a specific CXCL16 antibody (αCXCL16) which may also induce the intrinsic activity of tm- CXCL16, resulted in phosphorylation of both Akt and ERK1/2 (Fig. 2b, right side) after 20 min.…”

Section: Resultssupporting

confidence: 92%

“…Thereby, we verified this new mechanism beside its appearance in malignant glioma cells [10] in a different system, and showed that “inverse signaling” seems to be a broad biological process as it is also observable in more benign tumor cells.…”

Section: Resultsmentioning

confidence: 66%

“…In our recent investigations in cultured human glioma cells we proved the specificity of this effect by several different approaches [10]. Due to limited material and characteristics of cultured meningioma cells (e.g.…”

Section: Resultsmentioning

confidence: 99%

“…We recently discovered in highly malignant glioma cells a novel form of para- or autocrine signaling mechanism for transmembrane chemokines which we termed “inverse signaling” [10]. This new signaling concept anticipates that the proteolytically released chemokine domain ( s -chemokine) specifically binds to its transmembrane counterpart resulting in activation of intracellular kinases and induction of proliferation and anti-apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…gliomas, schwannomas, lung and breast tumors [5–9]. However, apart from its classical signaling mode in which the proteolytically released chemokine domain would bind to and signal via its receptor CXCR6, we recently discovered an alternate signaling mechanism for transmembrane chemokines in glioma cells which we termed “inverse signaling” [10]. According to this novel mechanism, the proteolytically released (or also recombinant) s- chemokine binds to an intact transmembrane chemokine specimen inducing intracellular signaling and biological effects independently from the expression of the receptor CXCR6.…”

Section: Introductionmentioning

confidence: 99%

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“Inverse signaling” of the transmembrane chemokine CXCL16 contributes to proliferative and anti-apoptotic effects in cultured human meningioma cells

Hattermann

Bartsch²,

Gebhardt

et al. 2016

Cell Commun Signal

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BackgroundChemokines and their receptors play a decisive role in tumor progression and metastasis. We recently found a new signaling mechanism in malignant glioma cells mediated by transmembrane chemokines that we termed “inverse signaling”. According to this hypothesis, soluble (s)-CXCL16 binds to the surface-expressed transmembrane (tm) -CXCL16, and induces signaling and different biological effects in the stimulated cells, so that the transmembrane ligand itself acts as a receptor for its soluble counterpart. Now, we hypothesized that “inverse signaling” via tm-CXCL16 might also take place in meningiomas, a completely different, benign tumor entity.MethodsWe used quantitative reverse-transcription polymerase chain reaction, immunocytochemistry and western blot to detect CXCL16 and CXCR6 in human meningioma cells isolated from 28 human meningiomas. Subsequently, we stimulated cultured human tm-CXCL16-positive, CXCR6-negative meningioma cells with recombinant s-CXCL16 and analyzed binding, signaling and biological effects using RNAi silencing to verify specificity.ResultsIn fact, cultured human meningioma cells considerably express CXCL16, but substantially lack CXCR6, the only known CXCL16 receptor. These receptor-negative cells could bind s-CXCL16, and responded to s-CXCL16 application with activation of the intracellular kinases ERK1/2 und Akt. As a consequence, we observed increased proliferation and rescue of apoptosis of cultured meningioma cells. Since binding and signaling were abolished by siRNA silencing, we concluded that tm-CXCL16 specifically acts as a receptor for s-CXCL16 also in human meningioma cells.ConclusionThese findings underline our recent report on the mechanism of inverse signaling as a broad biological process also observable in more benign tumor cells and contributing to tumor progression.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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“Inverse signaling” of the transmembrane chemokine CXCL16 contributes to proliferative and anti-apoptotic effects in cultured human meningioma cells

Hattermann

Bartsch²,

Gebhardt

et al. 2016

Cell Commun Signal

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Chemoattraction: Basic Concepts and Role in the Immune Response

Rodrı́guez-Fernández

Criado‐García

2021

Encyclopedia of Life Sciences

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In leucocytes, chemoattraction involves the detection of the direction of a chemical gradient of chemoattractants, a process called chemoattractant gradient sensing, followed by their migration towards the chemoattractant. Chemoattraction is called ‘chemotaxis’ when the chemoattractant gradient is soluble and ‘haptotaxis’ when this gradient is bound to the substrate. Chemoattraction plays a fundamental role in the regulation of the precise location of leucocytes during the immune response and consequently is fundamental for the adequate functioning of leucocytes in the immune system. Classical chemoattractants and chemokines use guanine nucleotide‐binding protein (G‐protein)‐coupled seven‐transmembrane‐spanning receptors (GPCRs) to relay intracellular signals that regulate chemoattraction. Apart from chemoattraction, chemoattractant receptors regulate additional functions in leucocytes that could also contribute to a correct immune response. Key Concepts Chemoattraction is defined as the orientation of a cell in the direction of a chemical gradient of ligands followed by the migration of the cells towards the chemoattractant. Chemoattractive factors are a diverse group of chemicals, including lipids, formylated peptides, proteolytic fragments of complement proteins and chemokines, with chemoattractive properties. Chemokines are small secreted proteins (8–14 kDa), which display a similar tertiary structure and potent chemoattractive abilities. Chemoattraction is regulated by chemoattractant receptors that are largely members of the G‐protein receptor‐coupled (GPCR) superfamily. GPCR chemoattractant members largely use Gi family proteins to regulate chemoattraction and other functions, although other G protein families can also be used. Chemoattractant receptors regulate not only chemoattraction but also a variety of additional functions in cells. Chemoattractant receptors are functionally divided into homeostatic receptors, which regulate homeostatic (e.g. chemotaxis, survival, migratory speed, cell shape changes and endocytosis) functions of cells, and inflammatory receptors, which control both homeostatic and inflammatory activities (e.g. generation of ROS, secretion of proteases, secretion of inflammatory cytokines and chemokines and formation of neutrophil extracellular trap (NET)).

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Glioma infiltration and extracellular matrix: key players and modulators

Ferrer

Moura‐Neto

Mentlein

2018

Glia

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155

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An outstanding characteristic of gliomas is their infiltration into brain parenchyma, a property that impairs complete surgical resection; consequently, these tumors might recur, resulting in a high mortality rate. Gliomas invade along preferential routes, such as those along white matter tracts and in the perineuronal and perivascular spaces. Brain extracellular components and their partners and modulators play a crucial role in glioma cell invasion. This review presents an extensive survey of the literature, showing how the brain extracellular matrix (ECM) is modulated during the glioma infiltration process. We explore aspects of ECM interaction with glioma cells, reviewing the main glycosaminoglycans, glycoproteins and proteoglycans. We discuss the roles of ECM-binding proteins, including CD44, RHAMM, integrins and axonal guidance molecules, and highlight the role of proteases and glycosidases in glioma infiltration; in binding and release chemokines, cytokines and growth factors; and in generating new bioactive ECM fragments. We also consider the roles of cytoskeletal signaling, angiogenesis, miRNAs and the glial-to-mesenchymal transition linked to glioma invasion. We closely discuss therapeutic approaches based on the modulation of the extracellular matrix, targeting the control of glioma infiltration, its relative failure in clinical trials, and potential means to overcome this difficulty.

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Transmembrane chemokines act as receptors in a novel mechanism termed inverse signaling

Cited by 23 publications

References 49 publications

“Inverse signaling” of the transmembrane chemokine CXCL16 contributes to proliferative and anti-apoptotic effects in cultured human meningioma cells

“Inverse signaling” of the transmembrane chemokine CXCL16 contributes to proliferative and anti-apoptotic effects in cultured human meningioma cells

Chemoattraction: Basic Concepts and Role in the Immune Response

Glioma infiltration and extracellular matrix: key players and modulators

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