Cooperation between integrin α5 and tetraspan TM4SF5 regulates VEGF-mediated angiogenic activity

Choi, Sungyeol; Lee, Sin Ae; Kwak, Tae Kyoung; Kim, Hyeon Jung; Lee, Mi Ji; Ye, Sang Kyu; Kim, Sung Hoon; Kim, Semi; Lee, Sang Eun

doi:10.1182/blood-2008-05-160671

Cited by 56 publications

(62 citation statements)

References 34 publications

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“…Src kinases are transducers of signals and are activated by various cell-surface receptors and interact with numerous substrates, mediating a wide range of biological events, such as growth [25], proliferation [31], angiogenesis [32], invasion [33], metastasis [12,34], chemoresistance [35] and bone turnover [36]. The abolition of Src signals using Src −/− mice or Src inhibitors significantly inhibits in vitro or in vivo tumor progression, suggesting Src as a therapeutic target for cancer therapy [4,5,27].…”

Section: Discussionmentioning

confidence: 99%

Denbinobin suppresses breast cancer metastasis through the inhibition of Src-mediated signaling pathways

Chen

Peng

Pai

et al. 2011

The Journal of Nutritional Biochemistry

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Section: Discussionmentioning

confidence: 99%

Denbinobin suppresses breast cancer metastasis through the inhibition of Src-mediated signaling pathways

Chen

Peng

Pai

et al. 2011

The Journal of Nutritional Biochemistry

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“…Through its association with tetraspanin, the ␣5␤1 integrin modulates VEGF/VEGFR function to facilitate VEGF-induced tumor angiogenesis (33). Integrin ␣4␤1, which forms a subfamily with ␣9␤1 sharing 40% amino acid sequence homology, also appears to interact with VEGF to modulate lymphangiogenesis (34).…”

Section: Discussionmentioning

confidence: 99%

Vascular Endothelial Growth Factor A (VEGF-A) Induces Endothelial and Cancer Cell Migration through Direct Binding to Integrin α9β1

Oommen

Gupta

Vlahakis

2011

Journal of Biological Chemistry

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Integrin ␣9␤1 mediates accelerated cell adhesion and migration through interactions with a number of diverse extracellular ligands. We have shown previously that it directly binds the vascular endothelial growth factors (VEGF) A, C, and D and contributes to VEGF-induced angiogenesis and lymphangiogenesis. Until now, the ␣9␤1 binding site in VEGF has not been identified. Here, we report that the three-amino acid sequence, EYP, encoded by exon 3 of VEGF-A is essential for binding of VEGF to integrin ␣9␤1 and induces adhesion and migration of endothelial and cancer cells. EYP is specific for ␣9␤1 binding and neither requires nor activates VEGFR-2, the cognate receptor for VEGF-A. Following binding to EYP, integrin ␣9␤1 transduces cell migration through direct activation of the integrin signaling intermediates Src and focal adhesion kinase. This interaction is biologically important because it mediates in vitro endothelial cell tube formation, wound healing, and cancer cell invasion. These novel findings identify EYP as a potential site for directed pharmacotherapy.The integrins are a diverse family of transmembrane heterodimeric adhesion receptors. They mediate outside-in and inside-out signaling through cell interactions with the extracellular matrix and in turn facilitate numerous processes such as cell adhesion, migration, and proliferation (1, 2). ␣9␤1 forms a small subfamily of integrins with ␣4␤1 and plays a specialized role in accelerated cell migration, for example more robust compared with ␣3␤1, ␣V␤3, and ␣5␤1 (3). Its biologic role was unclear until genetic deletion of the integrin in mice revealed a novel phenotype manifest by malnutrition and chylothoraces resulting in death 10 -12 days after birth (4). Ultimately, this phenotype was found to result in part from abnormal development of lymphatic valves (5) but also through disrupted direct ␣9␤1-VEGF-C/D interactions (6).The VEGF family of growth factors mediates many separate but overlapping functions, including inflammation and vascular permeability (7, 8), angiogenesis (VEGF-A), lymphangiogenesis (VEGF-C and D) (9), and carcinogenesis (10). VEGF-A undergoes alternative gene splicing resulting in multiple mature forms that share a VEGF homology domain and which interact with a wide array of common and unique partner proteins. VEGF-A165, the most common and well studied VEGF-A isoform, transduces its effects through binding of its canonical receptor, VEGFR-2 (9, 11). Following binding of VEGF-A, VEGFR-2 is autophosphorylated and subsequently internalized to endosomes and is either recycled to the cell surface in a functional state or trafficked to late endosomes and degraded (12).Although VEGF-A signals primarily through the VEGF receptors, it is also able to mediate its effects through interactions with other receptors, including integrins (3, 6, 13). Of particular note, we have reported that integrin ␣9␤1 is able to bind VEGF-C and D directly (6), which appears to explain partly the abnormal lymphatic development in the ␣9-null mouse. Subsequently, we...

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“…Integrins are widely expressed by both GBM cells and tumor vasculature. VEGF can trigger activation of endothelial integrins alpha (v) beta3 (αvβ3) [38]; tumor cell integrin αvβ3 activation promotes angiogenesis [39]. Primary endothelial cells undergo apoptosis when deprived from integrin-mediated attachment in vitro [40].…”

Section: Cilengitidementioning

confidence: 99%

Advances in the Treatment of Malignant Gliomas

2010

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Local control with surgery, radiation, and temozolomide chemotherapy remain the pillars of treatment for high-grade gliomas. Novel therapeutic strategies, including a variety of antiangiogenic agents, are under investigation. One of these agents, bevacizumab, was recently given accelerated approval by the US Food and Drug Administration as a single agent for recurrent glioblastoma. Recent trial results are generating important clinical questions regarding which patients to treat and when, and how best to monitor response. Encouraging results of recent studies are driving willingness to undertake aggressive treatment and to improve outcomes in this population. In this era, better understanding of biology, molecular aspects of cancer, and clinical trial methodology are crucial for clinicians. This review focuses on recent advances in the treatment malignant gliomas, especially antiangiogenic therapy.

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Cooperation between integrin α5 and tetraspan TM4SF5 regulates VEGF-mediated angiogenic activity

Cited by 56 publications

References 34 publications

Denbinobin suppresses breast cancer metastasis through the inhibition of Src-mediated signaling pathways

Denbinobin suppresses breast cancer metastasis through the inhibition of Src-mediated signaling pathways

Vascular Endothelial Growth Factor A (VEGF-A) Induces Endothelial and Cancer Cell Migration through Direct Binding to Integrin α9β1

Advances in the Treatment of Malignant Gliomas

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