Tetraspanin-3 is an organizer of the multi-subunit Nogo-A signaling complex

Thiede-Stan, Nina Kristin; Tews, Björn; Albrecht, David; Ristic, Zorica; Ewers, Helge

doi:10.1242/jcs.167981

Cited by 18 publications

(10 citation statements)

References 93 publications

(138 reference statements)

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“…This analysis yielded several insights: i) the intracellular domains of TSPAN12 are not predominantly important for function, ii) the large extracellular loop of TSPAN12 is required for association with the NDP receptor complex via FZD4, and iii) TSPAN12 incorporation into the NDP receptor complex is required for TSPAN12 function. In light of a recent study reporting that TSPAN3 modulates NOGO-A/S1PR2 GPCR signaling (Thiede-Stan et al, 2015), it appears that tetraspanin activity and GPCR receptor signaling intersect in multiple biological contexts.…”

Section: Discussionmentioning

confidence: 99%

TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

et al. 2017

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Summary Accessory proteins in Frizzled (FZD) receptor complexes are thought to determine ligand selectivity and signaling amplitude. Genetic evidence indicates that specific combinations of accessory proteins and ligands mediate vascular beta-catenin signaling in different CNS structures. In the retina, the tetraspanin TSPAN12 and the ligand norrin (NDP) mediate angiogenesis and both genes are linked to familial exudative vitreoretinopathy (FEVR). Yet, the molecular function of TSPAN12 remains poorly understood. Here, we report that TSPAN12 is an essential component of the NDP-receptor complex and interacts with FZD4 and NDP via its extracellular loops, consistent with an action as co-receptor that enhances FZD4 ligand selectivity for NDP. FEVR-linked mutations in TSPAN12 prevent the incorporation of TSPAN12 into the NDP-receptor complex. In vitro and in Xenopus embryos, TSPAN12 alleviates defects of FZD4 M105V, a mutation that destabilizes the NDP/FZD4 interaction. This study sheds light on the poorly understood function of accessory proteins in FZD signaling.

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Section: Discussionmentioning

confidence: 99%

TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

et al. 2017

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“…Tetraspanins also modulate intracellular signaling pathways by coordinating ligand-receptor binding at the cell surface. This is exemplified by the observation that tetraspanin 3 promotes binding of the NogoA ligand to the receptor sphingosine-1-phosphate-receptor-2 (S1PR2), which activates an intracellular signaling cascade leading to the inhibition of neurite outgrowth (Thiede-Stan et al, 2015). Most tetraspanins regulate the functions of their partner proteins by modulating their spatiotemporal distribution at the plasma membrane and organizing them together with other functional proteins (e.g., enzymes and substrates) (Odintsova et al, 2003; Haining et al, 2012; Thiede-Stan et al, 2015).…”

Section: Functions Of Tetraspaninsmentioning

confidence: 99%

“…This is exemplified by the observation that tetraspanin 3 promotes binding of the NogoA ligand to the receptor sphingosine-1-phosphate-receptor-2 (S1PR2), which activates an intracellular signaling cascade leading to the inhibition of neurite outgrowth (Thiede-Stan et al, 2015). Most tetraspanins regulate the functions of their partner proteins by modulating their spatiotemporal distribution at the plasma membrane and organizing them together with other functional proteins (e.g., enzymes and substrates) (Odintsova et al, 2003; Haining et al, 2012; Thiede-Stan et al, 2015). Recent studies, demonstrated that the interaction with tetraspanins influences the motility of their partner proteins and their association with other molecules within the plasma membrane (Yang et al, 2012; Mattila et al, 2013; Jouannet et al, 2015).…”

Section: Functions Of Tetraspaninsmentioning

confidence: 99%

The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein

Seipold

Säftig

2016

Front. Mol. Neurosci.

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Tetraspanins are a family of ubiquitously expressed and conserved proteins, which are characterized by four transmembrane domains and the formation of a short and a large extracellular loop (LEL). Through interaction with other tetraspanins and transmembrane proteins such as growth factors, receptors and integrins, tetraspanins build a wide ranging and membrane spanning protein network. Such tetraspanin-enriched microdomains (TEMs) contribute to the formation and stability of functional signaling complexes involved in cell activation, adhesion, motility, differentiation, and malignancy. There is increasing evidence showing that the tetraspanins also regulate the proteolysis of the amyloid precursor protein (APP) by physically interacting with the APP secretases. CD9, CD63, CD81, Tspan12, Tspan15 are among the tetraspanins involved in the intracellular transport and in the stabilization of the gamma secretase complex or ADAM10 as the major APP alpha secretase. They also directly regulate, most likely in concert with other tetraspanins, the proteolytic function of these membrane embedded enzymes. Despite the knowledge about the interaction of tetraspanins with the secretases not much is known about their physiological role, their importance in Alzheimer's Disease and their exact mode of action. This review aims to summarize the current knowledge and open questions regarding the biology of tetraspanins and the understanding how these proteins interact with APP processing pathways. Ultimately, it will be of interest if tetraspanins are suitable targets for future therapeutical approaches.

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“…This receptor was recently identified. In mammals, the GPCR S1PR2 is the signal transducing element of a receptor complex for Nogo‐A delta20 (Kempf et al, ; Thiede‐Stan et al, ). Our in situ hybridization experiments show that zebrafish RGCs express the homologue of S1PR2, as well as S1PR5a which is another member of the family.…”

Section: Discussionmentioning

confidence: 99%

Substrate properties of zebrafish Rtn4b/Nogo and axon regeneration in the zebrafish optic nerve

Bodrikov

Welte

Wiechers

et al. 2017

J of Comparative Neurology

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This study explored why lesioned retinal ganglion cell (RGC) axons regenerate successfully in the zebrafish optic nerve despite the presence of Rtn4b, the homologue of the rat neurite growth inhibitor RTN4-A/Nogo-A. Rat Nogo-A and zebrafish Rtn4b possess characteristic motifs (M1-4) in the Nogo-A-specific region, which contains delta20, the most inhibitory region of rat Nogo-A. To determine whether zebrafish M1-4 is inhibitory as rat M1-4 and Nogo-A delta20, proteins were recombinantly expressed and used as substrates for zebrafish single cell RGCs, mouse hippocampal neurons and goldfish, zebrafish and chick retinal explants. When offered as homogenous substrates, neurites of hippocampal neurons and of zebrafish single cell RGCs were inhibited by zebrafish M1-4, rat M1-4, and Nogo-A delta20. Neurite length increased when zebrafish single cell RGCs were treated with receptor-type-specific antagonists and, respectively, with morpholinos (MO) against S1PR2 and S1PR5a-which represent candidate zebrafish Nogo-A receptors. In a stripe assay, however, where M1-4 lanes alternate with polylysine-(Plys)-only lanes, RGC axons from goldfish, zebrafish, and chick retinal explants avoided rat M1-4 but freely crossed zebrafish M1-4 lanes-suggesting that zebrafish M1-4 is growth permissive and less inhibitory than rat M1-4. Moreover, immunostainings and dot blots of optic nerve and myelin showed that expression of Rtn4b is very low in tissue and myelin at 3-5 days after lesion when axons regenerate. Thus, Rtn4b seems to represent no major obstacle for axon regeneration in vivo because it is less inhibitory for RGC axons from retina explants, and because of its low abundance.

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Tetraspanin-3 is an organizer of the multi-subunit Nogo-A signaling complex

Cited by 18 publications

References 93 publications

TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

TSPAN12 Is a Norrin Co-receptor that Amplifies Frizzled4 Ligand Selectivity and Signaling

The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein

Substrate properties of zebrafish Rtn4b/Nogo and axon regeneration in the zebrafish optic nerve

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