Identification of the αvβ3 Integrin-interacting Motif of βig-h3 and Its Anti-angiogenic Effect

Nam, Ju Ock; Kim, Jung Eun; Jeong, Ha Won; Lee, Sung‐Jin; Lee, Byung Heon; Choi, Je Yong; Park, Rang Woon; Park, Jae Yong; Kim, In San

doi:10.1074/jbc.m300358200

Cited by 117 publications

(112 citation statements)

References 26 publications

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“…The four internal repeats region of Periostin share a homology with the axon guidance protein FAS1, containing sequences that allows binding of integrins and glycosaminoglycans in vivo (Elkins et al, 1990). FAS1 domains of big-h3, which shares a significant structural homology with Periostin, bear motifs interacting with integrins a3b1 and avb5 (Kim et al, 2000(Kim et al, , 2002 and mediate endothelial cell adhesion and migration via integrin avb3 (Nam et al, 2003). Similar to big-h3, we also previously found that interference with the function of integrins by specific anti-avb3 and anti-avb5 integrin antibodies had an effect on the ability of Periostin to mediate cell adhesion in OSCC cells (Kudo et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer

et al. 2006

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Oral squamous-cell carcinoma (OSCC) is one of the most common types of human cancer. Typically OSCC cells show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. We previously identified Periostin as the gene demonstrating the highest fold change expression in the invasive clone by comparing the transcriptional profile of parent OSCC cell line and a highly invasive clone. Here, we demonstrated that Periostin overexpression enhanced invasiveness in oral cancer cell lines. To know the role of Periostin in invasion, angiogenesis and metastasis in OSCC cases, we first examined the expression of Periostin mRNA in 31 OSCC cases by RT -PCR and Periostin protein in 74 OSCC cases by immunohistochemistry. Then, we compared the Periostin expression with invasion pattern, metastasis and blood vessel density. Periostin mRNA and protein overexpression were frequently found in OSCC cases and Periostin expression was well correlated with the invasion pattern and metastasis. Moreover, blood vessel density of Periostin-positive cases was higher than those of Periostin-negative cases. Interestingly, recombinant Periostin enhanced capillary formation in vitro in a concentration-dependant manner. In summary, these findings suggest that Periostin may promote invasion and angiogenesis in OSCC, and that Periostin can be a strong marker for prediction of metastasis in oral cancer patients.

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Section: Discussionmentioning

confidence: 99%

Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer

et al. 2006

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“…The YH18 motif of βig-h3 mediates the adhesion and growth of aortic VSMCs We have previously reported that the YH18 motif of βig-h3 mediates the adhesion of fibroblasts and endothelial cells through interaction with the αvβ5 and αvβ3 integrins, respectively Nam et al, 2003). In this regard, we investigated a protein motif(s) responsible for the adhesion of aortic VSMCs to βig-h3.…”

Section: Resultsmentioning

confidence: 99%

“…βig-h3 consists of four Fas-1 domains, which are designated as D-I, D-II, D-III, and D-IV domain Nam et al, 2003). Each domain has two conserved Fas-1 regions known as H1 and H2.…”

Section: Resultsmentioning

confidence: 99%

“…of vascular endothelial cells through the αvβ3 integrin, and a synthetic peptide containing the YH-18 motif of βig-h3 has anti-angiogenic activity by inhibiting the interaction between the αvβ3 integrin and βig-h3 (Nam et al, 2003). Given a key role of the αvβ5 integrin in VSMC migration on both βig-h3 and vitronectin that are elevated in atherosclerotic lesions, a function-blocking antibody against the αvβ5 integrin or a synthetic peptide containing the YH-18 motif could be a promising therapeutic approach against atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

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βig-h3 triggers signaling pathways mediating adhesion and migration of vascular smooth muscle cells through αvβ5 integrin

Lee

Bae²,

Park³

et al. 2006

Exp Mol Med

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Adhesion and migration of vascular smooth muscle cells (VSMCs) play an important role in the pathogenesis of atherosclerosis. These processes involve the interaction of VSMCs with extracellular matrix proteins. Here, we investigated integrin isoforms and signaling pathways mediating the adhesion and migration of VSMCs on βig-h3, a transforming growth factor (TGF)-β-inducible extracellular matrix protein that is elevated in atherosclerotic plaques. Adhesion assays showed that the αvβ5 integrin is a functional receptor for the adhesion of aortic VSMCs to βig-h3. An YH18 motif containing amino acids between 563 and 580 of βig-h3 was an essential motif for the adhesion and growth of VSMCs. Interaction between the YH18 motif and the αvβ5 integrin was responsible for the migration of VSMCs on βig-h3. Inhibitors of phosphatidylinositide 3-kinase, extracellular signalregulated kinase (ERK), and Src kinase reduced the adhesion and migration of VSMCs on βig-h3. βig-h3 triggered phosphorylation and activation of AKT, ERK, focal adhesion kinase, and paxillin mediating the adhesion and migration of VSMCs. Taken together, these results suggest that βig-h3 and αvβ5 integrin play a role in the adhesion and migration of VSMCs during the pathogenesis of atherosclerosis.

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“…Adhesion-To assess the involvement of ␤3 and ␤1 integrins in the observed IGF-IR phosphorylation, we applied neutralizing anti-␤3 and anti-␤1 antibodies that were shown before to prevent interaction of fibronectin with the corresponding integrins (24,25). The fibronectin-induced increase in phosphorylation of IGF-IR was abolished in cells cultured on fibronectin in the presence of the ␤3 blocking antibody (Fig.…”

Section: ␤3 Integrin Mediates the Fibronectin-induced Phosphorylationmentioning

confidence: 99%

Insulin-like Growth Factor-I Receptor Mediates the Prosurvival Effect of Fibronectin

Edderkaoui

Hong

Lee

et al. 2007

Journal of Biological Chemistry

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We recently showed that extracellular matrix (ECM) proteins, which are abundant in desmoplastic pancreatic tumor, are as potent as growth factors in inhibiting apoptosis in pancreatic cancer (PaCa) cells. Here we show that fibronectin, a major ECM component, engages insulin-like growth factor-I receptor (IGF-IR) to inhibit PaCa cell death. We found that fibronectin-induced protection from apoptosis is fully mediated by IGF-IR and is independent of IGF-I. Pharmacologic and molecular inhibitions of IGF-IR stimulated apoptosis and prevented the prosurvival effect of fibronectin in PaCa cells. Our data indicate that fibronectin protects from apoptosis through trans-activation of IGF-IR. We showed that fibronectin stimulated complex formation between its receptor ␤3 integrin and protein-tyrosine phosphatase SHP-2. This process of complex formation, in turn, pre- Pancreatic cancer is the fourth most common cause of death in western countries with almost the same rate of incidence and mortality per year (1, 2). The disease is very resistant to radioand/or chemotherapies. One reason for that is the resistance of pancreatic cancer (PaCa) 2 cells to apoptosis (3).Pancreatic adenocarcinoma is a fibrotic tumor, which is characterized by a high level of extracellular matrix (ECM) proteins. ECM mediates adhesion and invasiveness of cancer cells. Cell survival also depends on adequate connections with ECM proteins through specific integrin receptors. We recently showed that ECM proteins are key mediators of PaCa cell survival (4, 5) and that detachment from ECM stimulates PaCa cell death. The mechanisms through which ECM proteins protect PaCa cells from death are not fully understood.Fibronectin is a major ECM protein of pancreatic adenocarcinoma; its receptors, ␤3 and ␤1 integrins, are up-regulated in pancreatic cancer cells (6). Fibronectin stimulates invasion and adhesion and markedly increases survival of pancreatic cancer cells (7,8).The importance of fibronectin and other extracellular matrix proteins in pancreatic cancer is underscored by several findings. Pancreatic adenocarcinoma is one of the most lethal of human cancers with a 5-year survival rate of less than 5% (9). This cancer has a characteristic of marked desmoplasia, which is a remarkable increase in extracellular matrix that infiltrates and envelopes the cancer (10). Importantly there is at least one report that demonstrates that greater amounts of intratumor extracellular matrix in pancreatic cancer patients are correlated with more aggressive disease and more rapid death (11). Finally recent studies in animal models of pancreatic cancer show that tumors grow more rapidly when the fibroblastic cells of the cancer called stellate cells are included in inocula with cancer cells (12). The addition of the stellate cells results in the experimental tumors taking on the characteristics of the human cancer with the extracellular matrix infiltrating and enveloping the cancer cells.In addition, another powerful mediator of PaCa cell survival is insulin-like growth fa...

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Identification of the αvβ3 Integrin-interacting Motif of βig-h3 and Its Anti-angiogenic Effect

Cited by 117 publications

References 26 publications

Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer

Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer

βig-h3 triggers signaling pathways mediating adhesion and migration of vascular smooth muscle cells through αvβ5 integrin

Insulin-like Growth Factor-I Receptor Mediates the Prosurvival Effect of Fibronectin

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