Tetraspanin CD63 Promotes Vascular Endothelial Growth Factor Receptor 2-β1 Integrin Complex Formation, Thereby Regulating Activation and Downstream Signaling in Endothelial Cells in Vitro and in Vivo

Tugues, Sònia; Honjo, Satoshi; König, Christian; Padhan, Narendra; Kroon, Jeffrey; Gualandi, Laura; Li, Xiujuan; Barkefors, Irmeli; Thijssen, Victor L.; Griffioen, Arjan W.; Claesson‐Welsh, Lena

doi:10.1074/jbc.m113.468199

Cited by 54 publications

(53 citation statements)

References 51 publications

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“…Therefore, it is not surprising that VEGFR2 is involved in a similar type of interplay with β1 integrin. Several studies demonstrated a synergism between β1 integrin-dependent adhesive functions and downstream VEGFR2 signaling [57,58 ■■ ]. Mechanistically, this synergism is mediated by tetraspanin CD63, which interacts with both β1 integrin and VEGFR2, and serves as a critical regulator of the complex between these two signaling components.…”

Section: Regulation Of Integrin Function By Interactions With Other Cmentioning

confidence: 99%

“…Mechanistically, this synergism is mediated by tetraspanin CD63, which interacts with both β1 integrin and VEGFR2, and serves as a critical regulator of the complex between these two signaling components. Silencing of CD63 disrupts the β1 integrin/VEGFR2 complex leading to deficient VEGFR2 activation and impaired endothelial adhesion and migration [58 ■■ ]. …”

Section: Regulation Of Integrin Function By Interactions With Other Cmentioning

confidence: 99%

“…Clustering of different types of receptors leads to assembly of large signaling complexes, containing prominent intracellular adapter proteins and kinases, thereby creating favorable conditions for direct and indirect cross-activation of receptors. One of the most prominent players in this convergence of integrin and growth factor signaling pathways is c-src kinase [49,56 ■■ ,58 ■■ ]. Considering that each individual integrin or growth factor receptor has its own spectrum of binding partners, the numbers of molecules within these complexes might increase exponentially, thereby multiplying the possibilities of cross-activation and/or cross-inhibition of these receptors.…”

Section: Regulation Of Integrin Function By Interactions With Other Cmentioning

confidence: 99%

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Integrin function in vascular biology

Plow

Meller

Byzova

2014

Current Opinion in Hematology

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Purpose of review This review considers recent developments concerning the role of integrins in vascular biology with a specific emphasis on integrin activation, and the crosstalk between integrins and growth factor receptors. Recent findings Recent studies have shown leukocytes can mediate direct transfer of molecules into endothelial cells, how specific integrins can be used to transduce signaling events, in particular in vascular beds, and how endothelial cell integrins can be targeted with specific ligands for the delivery of therapeutics. Kindlin and talin are both essential for integrin activation based on in-vivo studies of mice and humans in which the genes encoding for these proteins have been inactivated. Recent studies have attempted to translate these in-vivo realities into in-vitro models with mixed results. Summary Mechanisms and consequences of integrin–ligand interactions on blood and vascular cells remain a major topic of hematological research. Crucial to the ligand binding function of integrins are two intracellular binding partners, talin and kindlin. In seeking to define the molecular basis for `integrin activation', a mechanism must be envisioned in which both proteins talin and kindlin are required to produce a productive functional response, be it platelet aggregation or leukocyte extravasation. On endothelial cells, integrins and vascular endothelial growth factor receptor 2 influence the activation of one another by virtue of their direct physical interaction. It has been shown that this bidirectional communication is subject to regulation during angiogenesis.

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Section: Regulation Of Integrin Function By Interactions With Other Cmentioning

confidence: 99%

Section: Regulation Of Integrin Function By Interactions With Other Cmentioning

confidence: 99%

Section: Regulation Of Integrin Function By Interactions With Other Cmentioning

confidence: 99%

See 1 more Smart Citation

Integrin function in vascular biology

Plow

Meller

Byzova

2014

Current Opinion in Hematology

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“…For example, complex formation between CD63 and the gastric H,K-ATPase b-subunit results in the redistribution of H, K-ATPase from the cell surface to CD63-positive intracellular compartments (11). Furthermore, CD63 has been described to regulate surface expression of membrane-type 1 matrix metalloproteinase by targeting the enzyme for lysosomal degradation (12), and silencing of CD63 in endothelial cells prevents internalization of vascular endothelial growth factor receptor 2 (VEGFR2) in response to its ligand VEGF (13). Also across different tumor types, CD63 has been demonstrated to continuously shuttle between the plasma membrane and lysosomes, which was dependent on the presence of AP2 and clathrin (14).…”

Section: Introductionmentioning

confidence: 99%

Efficient Payload Delivery by a Bispecific Antibody–Drug Conjugate Targeting HER2 and CD63

Goeij

Vink

Napel

et al. 2016

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) are designed to be stable in circulation and to release potent cytotoxic drugs intracellularly following antigen-specific binding, uptake, and degradation in tumor cells. Efficient internalization and routing to lysosomes where proteolysis can take place is therefore essential. For many cell surface proteins and carbohydrate structures on tumor cells, however, the magnitude of these processes is insufficient to allow for an effective ADC approach. We hypothesized that we could overcome this limitation by enhancing lysosomal ADC delivery via a bispecific antibody (bsAb) approach, in which one binding domain would provide tumor specificity, whereas the other binding domain would facilitate targeting to the lysosomal compartment. We therefore designed a bsAb in which one binding arm specifically targeted CD63, a protein that is described to shuttle between the plasma membrane and intracellular compartments, and combined it in a bsAb with a HER2 binding arm, which was selected as model antigen for tumor-specific binding. The resulting bsHER2xCD63 his demonstrated strong binding, internalization and lysosomal accumulation in HER2-positive tumor cells, and minimal internalization into HER2-negative cells. By conjugating bsHER2xCD63 his to the microtubule-disrupting agent duostatin-3, we were able to demonstrate potent cytotoxicity of bsHER2xCD63 his -ADC against HER2-positive tumors, which was not observed with monovalent HER2-and CD63-specific ADCs. Our data demonstrate, for the first time, that intracellular trafficking of ADCs can be improved using a bsAb approach that targets the lysosomal membrane protein CD63 and provide a rationale for the development of novel bsADCs that combine tumor-specific targeting with targeting of rapidly internalizing antigens. Mol Cancer Ther; 15(11); 2688-97. Ó2016 AACR.

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“…Furthermore, tumor cells overexpressing rat TSPAN8 promote endothelial cell branching in vitro and induce systemic angiogenesis in vivo; these effects are driven by selective uptake of tumor cell-derived, TSPAN8-containing exosomes by endothelial cells, a process directed by exosomal TSPAN8. 112,113 Other tetraspanins implicated in endothelial cell migration and possibly angiogenesis include CD81 and CD63, which have been identified as positive regulators, 96,114 and CD82, which has been reported as a negative regulator. 115 Therefore, accumulating evidence indicates that targeting specific tetraspanins may hold promise as a novel treatment for cancer and other conditions involving angiogenesis, such as macular degeneration and postischemic revascularization.…”

mentioning

confidence: 99%

Tetraspanins in Cell Migration

Jiang¹,

Zhang

Huang

2015

Cell Adhesion & Migration

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mitogen-activated protein kinase; HCC, hepatocellular carcinoma; cdc42, cell division control protein 42; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Sprouty2, Sprouty homolog 2; ROCK, Rho-associated protein kinase; PI3K, phosphatidylinositol-4, 5-bisphosphate 3-kinase; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; eNOS, endothelial nitric oxide synthase; HUVECs, human umbilical vein endothelial cells.Tetraspanins are a superfamily of small transmembrane proteins that are expressed in almost all eukaryotic cells. Through interacting with one another and with other membrane and intracellular proteins, tetraspanins regulate a wide range of proteins such as integrins, cell surface receptors, and signaling molecules, and thereby engage in diverse cellular processes ranging from cell adhesion and migration to proliferation and differentiation. In particular, tetraspanins modulate the function of proteins involved in all determining factors of cell migration including cell-cell adhesion, cell-ECM adhesion, cytoskeletal protrusion/ contraction, and proteolytic ECM remodeling. We herein provide a brief overview of collective in vitro and in vivo studies of tetraspanins to illustrate their regulatory functions in the migration and trafficking of cancer cells, vascular endothelial cells, skin cells (keratinocytes and fibroblasts), and leukocytes. We also discuss the involvement of tetraspanins in various pathologic and remedial processes that rely on cell migration and their potential value as targets for therapeutic intervention.

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Tetraspanin CD63 Promotes Vascular Endothelial Growth Factor Receptor 2-β1 Integrin Complex Formation, Thereby Regulating Activation and Downstream Signaling in Endothelial Cells in Vitro and in Vivo

Cited by 54 publications

References 51 publications

Integrin function in vascular biology

Integrin function in vascular biology

Efficient Payload Delivery by a Bispecific Antibody–Drug Conjugate Targeting HER2 and CD63

Tetraspanins in Cell Migration

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