Peptides derived from the integrin β cytoplasmic tails inhibit angiogenesis

Cao, Zhongyuan; Suo, Xinfeng; Chu, Yudan; Zhou, Xu; Bao, Yun; Miao, Chunxiao; Deng, Wei; Mao, Kaijun; Gao, Juan; Xu, Zhen; Ma, Yanqing

doi:10.1186/s12964-018-0248-8

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…Integrin β3 plays a critical role in pathological angiogenesis 40,41 . β3‐endonexin is a binding partner for the integrin β3 and is able to enhance HUVEC tube formation but is not required for VEGF‐induced HUVEC adhesion and migration 41 . In the present study, the integrin β3 in HUVEC was significantly reduced by LN229 conditioned medium.…”

Section: Resultssupporting

confidence: 43%

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PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

et al. 2020

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Glioblastoma, also known as glioblastoma multiforme (GBM), is a fast‐growing tumor and the most aggressive brain malignancy. Proteasome subunit beta type‐8 (PSMB8) is one of the 17 essential subunits for the complete assembly of the 20S proteasome complex. The aim of the present study was to evaluate the role of PSMB8 expression in GBM progression and angiogenesis. PSMB8 expression in glioblastoma LN229 and U87MG was knocked down by siRNA or inducible shRNA both in vitro and in vivo. After PSMB8 reduction, cell survival, migration, invasion, angiogenesis, and the related signaling cascades were evaluated. An orthotopic mouse tumor model was also provided to examine the angiogenesis within tumors. A GEO profile analysis indicated that high expression of PSMB8 mRNA in GBM patients was correlated with a low survival rate. In immunohistochemistry analysis, PSMB8 expression was higher in high‐grade than in low‐grade brain tumors. The proliferation, migration, and angiogenesis of human GBM cells were decreased by PSMB8 knockdown in vitro. Furthermore, phosphorylated focal adhesion kinase (p‐FAK), p‐paxillin, MMP2, MMP9, and cathepsin B were significantly reduced in LN229 cells. Integrin β1 and β3 were reduced in HUVEC after incubation with LN229‐conditioned medium. In an orthotopic mouse tumor model, inducible knockdown of PSMB8 reduced the expression of vascular endothelial growth factor (VEGF), VEGF receptor, and CD31 as well as the progression of human glioblastoma. In this article, we demonstrated the role of PSMB8 in glioblastoma progression, especially neovascularization in vitro and in vivo. These results may provide a target for the anti–angiogenic effect of PSMB8 in glioblastoma therapy in the future.

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Section: Resultssupporting

confidence: 43%

“…The migration ability of HUVEC was not affected by knockdown PSMB8 in glioblastoma cells. Integrin β3 plays a critical role in pathological angiogenesis 40,41 . β3‐endonexin is a binding partner for the integrin β3 and is able to enhance HUVEC tube formation but is not required for VEGF‐induced HUVEC adhesion and migration 41 .…”

Section: Resultsmentioning

confidence: 99%

PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

et al. 2020

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“…However, neither of them inhibited kindlin‐3‐PH binding to phospholipids (data not shown), suggesting that the inhibitory effect of K3PH‐L on paxillin binding to the PH domain of kindlin‐3 is specific. To perform functional analysis for platelets, these peptides were N‐terminally fused with a membrane‐penetrating amino‐acid sequence (TAT), as previously described 42 (Figure 5A). As shown in Figure 5C, neither TAT‐K3PH‐L nor TAT‐K3PH‐L‐M2 inhibited soluble fibrinogen binding to human platelets upon stimulation with either thrombin activator peptide 6 (TRAP‐6) or collagen‐related peptide (CRP).…”

Section: Resultsmentioning

confidence: 99%

Paxillin binding to the PH domain of kindlin‐3 in platelets is required to support integrin αIIbβ3 outside‐in signaling

Nguyen

Shi

et al. 2021

Journal of Thrombosis and Haemostasis

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Background Kindlin‐3 is essential for supporting the bidirectional signaling of integrin αIIbβ3 in platelets by bridging the crosstalk between integrin αIIbβ3 and the cytoplasmic signaling adaptors. Objective In this study, we identified a previously unrecognized paxillin binding site in the pleckstrin homology (PH) domain of kindlin‐3 and verified its functional significance. Methods Structure‐based approaches were employed to identify the paxillin binding site in the PH domain of kindlin‐3. In addition, the bidirectional signaling of integrin αIIbβ3 were evaluated in both human and mouse platelets. Results In brief, we found that a β1‐β2 loop in the PH domain of kindlin‐3, an important part of the canonical membrane phospholipid binding pocket, was also involved in mediating paxillin interaction. Interestingly, the binding sites of paxillin and membrane phospholipids in the PH domain of kindlin‐3 were mutually exclusive. Specific disruption of paxillin binding to the PH domain by point mutations inhibited platelet spreading on immobilized fibrinogen while having no inhibition on soluble fibrinogen binding to stimulated platelets. In addition, a membrane‐permeable peptide derived from the β1‐β2 loop in the PH domain of kindlin‐3 was capable of inhibiting platelet spreading and clot retraction, but it had no effect on soluble fibrinogen binding to platelets and platelet aggregation. Treatment with this peptide significantly reduced thrombus formation in mice. Conclusion Taken together, these findings suggest that interaction between paxillin and the PH domain of kindlin‐3 plays an important role in supporting integrin αIIbβ3 outside‐in signaling in platelets, thus providing a novel antithrombotic target.

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“…To demonstrate the analysis of various data for IDR and MemMoRF validation and phosphorylation-dependent regulatory disorder-to-order transition, we selected integrin β3, which plays a role in angiogenesis and tumor growth ( 44 , 45 ). Targeting integrin β3 associated signalling was shown to induce apoptosis of endothelial tumor cells ( 44 ) and cell permeable peptides derived from integrin β cytoplasmic tails (CT) were developed for angiogenesis inhibition ( 46 ). Since these peptides overlap with a MemMoRF, a detailed description of phosphorylation dependent protein and membrane interactions of this region will help to improve the potential therapeutic use of integrin β CT peptides.…”

Section: Identification and Systematic Collection Of Memmorfsmentioning

confidence: 99%

The MemMoRF database for recognizing disordered protein regions interacting with cellular membranes

Csizmadia

Erdős

Tordai

et al. 2020

Nucleic Acids Research

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Protein and lipid membrane interactions play fundamental roles in a large number of cellular processes (e.g. signalling, vesicle trafficking, or viral invasion). A growing number of examples indicate that such interactions can also rely on intrinsically disordered protein regions (IDRs), which can form specific reversible interactions not only with proteins but also with lipids. We named IDRs involved in such membrane lipid-induced disorder-to-order transition as MemMoRFs, in an analogy to IDRs exhibiting disorder-to-order transition upon interaction with protein partners termed Molecular Recognition Features (MoRFs). Currently, both the experimental detection and computational characterization of MemMoRFs are challenging, and information about these regions are scattered in the literature. To facilitate the related investigations we generated a comprehensive database of experimentally validated MemMoRFs based on manual curation of literature and structural data. To characterize the dynamics of MemMoRFs, secondary structure propensity and flexibility calculated from nuclear magnetic resonance chemical shifts were incorporated into the database. These data were supplemented by inclusion of sentences from papers, functional data and disease-related information. The MemMoRF database can be accessed via a user-friendly interface at https://memmorf.hegelab.org, potentially providing a central resource for the characterization of disordered regions in transmembrane and membrane-associated proteins.

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Peptides derived from the integrin β cytoplasmic tails inhibit angiogenesis

Cited by 8 publications

References 46 publications

PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

PSMB8 inhibition decreases tumor angiogenesis in glioblastoma through vascular endothelial growth factor A reduction

Paxillin binding to the PH domain of kindlin‐3 in platelets is required to support integrin αIIbβ3 outside‐in signaling

The MemMoRF database for recognizing disordered protein regions interacting with cellular membranes

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