Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated by EphB2

Okumura, Fumihiro; Akiko, Joo-Okumura; Obara, Keisuke; Petersen, Alexander M.; Nishikimi, Akihiko; Fukui, Yoshihiro; Nakatsukasa, Kunio; Kamura, Takumi

doi:10.1091/mbc.e17-07-0450

Cited by 15 publications

(15 citation statements)

References 53 publications

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“…The endosomal internalisation of ephrin:Eph complexes is required for normal receptor signalling 15–17 , and eventually leads to dephosphorylation of juxtamembrane tyrosines 18 , ubiquitylation of the Eph cytoplasmic tail 19 , and Eph recycling or degradation 20 . It is unknown whether the fate of internalised Eph receptors depends on the ESCRT machinery, which detects ubiquitylated receptors and transfers them between specialised vesicles, where they are sorted back to the membrane or to the lysosome 2,21 .…”

Section: Introductionmentioning

confidence: 99%

The endosomal sorting adaptor HD-PTP is required for ephrin-B:EphB signalling in cellular collapse and spinal motor axon guidance

Lahaie

Morales

Bagci

et al. 2019

Sci Rep

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The signalling output of many transmembrane receptors that mediate cell-cell communication is restricted by the endosomal sorting complex required for transport (ESCRT), but the impact of this machinery on Eph tyrosine kinase receptor function is unknown. We identified the ESCRT-associated adaptor protein HD-PTP as part of an EphB2 proximity-dependent biotin identification (BioID) interactome, and confirmed this association using co-immunoprecipitation. HD-PTP loss attenuates the ephrin-B2:EphB2 signalling-induced collapse of cultured cells and axonal growth cones, and results in aberrant guidance of chick spinal motor neuron axons in vivo . HD-PTP depletion abrogates ephrin-B2-induced EphB2 clustering, and EphB2 and Src family kinase activation. HD-PTP loss also accelerates ligand-induced EphB2 degradation, contrasting the effects of HD-PTP loss on the relay of signals from other cell surface receptors. Our results link Eph function to the ESCRT machinery and demonstrate a role for HD-PTP in the earliest steps of ephrin-B:EphB signalling, as well as in obstructing premature receptor depletion.

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Section: Introductionmentioning

confidence: 99%

The endosomal sorting adaptor HD-PTP is required for ephrin-B:EphB signalling in cellular collapse and spinal motor axon guidance

Lahaie

Morales

Bagci

et al. 2019

Sci Rep

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“…The SPRY domain, which more than 150 human proteins contain, was discovered as a sequence repeat responsible for protein-protein interactions [33]. The SPRY domain of SPSB proteins interacts with many cellular proteins such as Par-4, c-Met, hnRNP A1, iNOS, TβRII, SNAIL, and EphB2[23–26,34–36]. In this study, we first identified viral proteins HCV E1 and NS5A as those interacting with the SPRY domain of SPSB2.…”

Section: Discussionmentioning

confidence: 99%

“…SPSB3 targets SNAIL for polyubiquitination and proteasomal degradation to suppress tumor metastasis in various kinds of cancer, suggesting the vital role of SPSB3 in regulating epithelial-mesenchymal transition and cancer progression [25]. SPSB4 plays a crucial role in regulating cellular repulsive responses through interacting with and targeting EphB2 for degradation [26].…”

Section: Introductionmentioning

confidence: 99%

SPSB2 inhibits hepatitis C virus replication by targeting NS5A for ubiquitination and degradation

Wang

Liu

et al. 2019

PLoS ONE

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Hepatitis C virus (HCV) replication involves many viral and host factors. Host factor SPRY domain- and SOCS box-containing protein 2(SPSB2) belongs to SPSB family, and it recruits target proteins by the SPRY domain and forms E3 ubiquitin ligase complexes by the SOCS box. As an adaptor protein, it can regulate the host’s response to infection, but little is known about whether SPSB2 plays a role in HCV replication. In the present study, we found that HCV infection significantly upregulated the mRNA and protein levels of SPSB2 in HCVcc-infected cells. Exogenous expression of SPSB2 in hepatoma cells decreased HCV RNA and protein levels which depended on the SOCS box, while knockdown of endogenous SPSB2 increased HCV RNA and protein levels. Additionally, we demonstrated that SPSB2 interacted with HCV structural protein E1 and nonstructural protein protein 5A (NS5A) via the C-terminal portion of the SPSB2 SPRY domain. Furthermore, SPSB2 induced NS5A ubiquitination and mediated NS5A degradation. Collectively, this study discovered host factor SPSB2 significantly inhibits HCV replication by interacting and degrading NS5A.

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“…Indeed, two studies show that EphB receptors are ubiquitylated in response to ligand binding. EphB2 is ubiquitylated by the SOCS box protein SPSB4, whose loss accentuates ephrin-B2-induced repulsive cellular responses (Okumura et al, 2017), and the ligand-induced kinase activity of EphB1 promotes its ubiquitylation by Cbl (Fasen et al, 2008). Therefore, an alternative model of HD-PTP function may involve its recruitment of deubiquitylases that counterbalance ephrin-B-induced EphB ubiquitylation, as well as promoting its recycling, since deubiquitylated Eph receptors are more likely to be recycled (Sabet et al, 2015).…”

Section: Hd-ptp: a New And Potent Effector Of Eph Signallingmentioning

confidence: 99%

“…The endosomal internalisation of ephrin:Eph receptor complexes is required for their normal signalling (Marston et al, 2003;Zimmer et al, 2003, Cowan et al, 2005, and eventually leads to dephosphorylation of juxtamembrane tyrosines (Shintani et al, 2006), ubiquitylation of the Eph cytoplasmic tail (Okumura et al, 2017) and Eph recycling or degradation (Sabet et al, 2015). It is unknown whether the fate of internalised Eph receptors depends on the ESCRT machinery, which detects ubiquitylated receptors and transfers them between specialised vesicles where they are subject to deubiquitylation, and sorting to the lysosome (Raiborg & Stenmark, 2009;Szymanska et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The endosomal sorting adaptor HD-PTP is required for ephrin-B:EphB signalling in cell collapse and motor axon guidance

Lahaie

Morales

Bagci

et al. 2018

Preprint

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The signalling output of many transmembrane receptors that mediate cell-cell communication is restricted by the endosomal sorting complex required for transport (ESCRT), but the impact of this machinery on Eph tyrosine kinase receptor function is unknown. We identified the ESCRT-associated adaptor protein HD-PTP as part of an EphB2 BioID interactome, and confirmed this association using co-immunoprecipitation. Although HD-PTP loss does not change EphB2 expression, it attenuates the ephrin-B2:EphB2 signalling-induced collapse of cultured cells and axonal growth cones, and results in aberrant guidance of chick spinal motor neuron axons in vivo HD-PTP depletion abrogates ligand-induced EphB2 clustering, and EphB2 and Src family kinase activation. HD-PTP deficiency also accelerates ligand-induced EphB2 degradation, contrasting the phenotypes reported for other cell surface receptors. Our results link Eph signalling to the ESCRT machinery and demonstrate a role for HD-PTP in the earliest steps of ephrin-B:EphB signalling, as well as in obstructing premature receptor depletion.

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Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated by EphB2

Cited by 15 publications

References 53 publications

The endosomal sorting adaptor HD-PTP is required for ephrin-B:EphB signalling in cellular collapse and spinal motor axon guidance

The endosomal sorting adaptor HD-PTP is required for ephrin-B:EphB signalling in cellular collapse and spinal motor axon guidance

SPSB2 inhibits hepatitis C virus replication by targeting NS5A for ubiquitination and degradation

The endosomal sorting adaptor HD-PTP is required for ephrin-B:EphB signalling in cell collapse and motor axon guidance

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