Identification of a Novel Integrin αvβ3 Binding Site in CCN1 (CYR61) Critical for Pro-angiogenic Activities in Vascular Endothelial Cells

Chen, Ningyu; Leu, Shr Jeng Jim; Todorović, Viktor; Lam, Stephen; Lau, Lester F.

doi:10.1074/jbc.m406813200

Cited by 121 publications

(146 citation statements)

References 59 publications

(86 reference statements)

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“…CCN1 promotes migration, adhesion, angiogenesis and tumor growth through an integrin-dependent mechanism (Babic et al 1998;Chen et al 2004). In the case of prostate carcinoma cells, CCN1 has been shown to be essential for proliferation (Franzen et al 2009).…”

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confidence: 99%

CCN1: a novel target for pancreatic cancer

Leask

2011

J. Cell Commun. Signal.

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Members of CCN family of matricellular proteins are being increasingly recognized by the translational research community as representing excellent targets for drug intervention. Although much effort has been expended in outlining the mechanisms involved in pancreatic carcinogenesis, the precise molecular pathways involved remain incompletely understood, and appropriate targets for drug intervention remain elusive. A recent exciting report by Haque and colleagues (Mol Cancer. 2011 Jan 13;10:8) provides strong evidence that CCN1 (cyr61) is a potential therapeutic target in pancreatic cancer.

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confidence: 99%

CCN1: a novel target for pancreatic cancer

Leask

2011

J. Cell Commun. Signal.

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“…1-3). The CCN proteins are multifunctional and are involved in cell adhesion, angiogenesis, cell differentiation, and tumorigenesis (4)(5)(6)(7)(8). CTGF was first identified as a mitogen from human umbilical vein endothelial cells, and expression of CTGF is inducible by tumor growth factor-h in fibroblasts (9).…”

Section: Introductionmentioning

confidence: 99%

Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non–Small Cell Lung Cancer Cells

Chien¹,

Ding²,

Gui

et al. 2006

Molecular Cancer Research

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Connective tissue growth factor (CTGF) is a secreted protein that belongs to CCN family. The proteins in this family are implicated in various biological processes, such as angiogenesis, adhesion, migration, and apoptosis. In this study, we explored the roles of CTGF in lung tumorigenesis. The expression levels of CTGF in 58 lung cancer samples were reduced by >2 fold in 57% of the samples compared with matched normal samples using real-time reverse transcription-PCR. These results were confirmed by immunohistochemical staining for CTGF in normal lung epithelia and lung cancer. Cellular proliferation was inhibited in non -small cell lung cancer (NSCLC) cell lines NCI-H460, NCI-H520, NCI-H1299, and SK-MES-1 by CTGF overexpression. Partially purified CTGF suppressed lung cancer cell growth. The growth inhibition caused by CTGF overexpression was associated with growth arrest at G 0 -G 1 and prominent induction of p53 and ADP ribosylation factor. Most interestingly, overexpression of CTGF suppressed insulin-like growth factor-I -dependent Akt phosphorylation and epidermal growth factordependent extracellular signal-regulated kinase 1/2 phosphorylation. In summary, NSCLC cells expressed decreased levels of CTGF compared with normal lung cells; this lower expression has an effect on lung cancer cell proliferation and its cellular response to growth factors. Our data suggest that CTGF may behave as a secreted tumor suppressor protein in the normal lung, and its expression is suppressed in many NSCLCs.

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“…The primary sequence of CCN5 does not contain the RGD recognition motif present integrin α v β 3 ligands such as vitronectin, fibronectin, fibrinogen, thrombospondin, and osteopontin (Ruoslahti & Pierschbacher 1987). In addition to CCN5, at least three other integrin α v β 3 ligands do not contain the consensus RGD sequence: a cell surface molecule from the immunoglobulin superfamily CD31/PECAM-1 (Piali et al 1995), the matrix metalloproteinase MMP-2 (Brooks et al 1996), and the CCN family member CCN1 (Chen et al 2004). Interestingly, CCN5 contains a stretch of amino acids in its von Willebrand Factor-C domain that is very similar to a known integrin α v β 3 binding site in CCN1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, CCN5 contains a stretch of amino acids in its von Willebrand Factor-C domain that is very similar to a known integrin α v β 3 binding site in CCN1 (Fig. 1) (Chen et al 2004).…”

Section: Discussionmentioning

confidence: 99%

“…One shRNA used the following oligos: (Chen et al 2004) is critical for CCN1 binding to integrin α v β 3 . CCN5 has an analogous region in amino acids 116-135 that contains Asp-125 as well flanking Cys residues (shown in red), which are necessary for binding of CCN1 to integrin α v β 3 as well as other conserved Cys residues (shown in blue) enhance binding affinity…”

Section: Methodsmentioning

confidence: 99%

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The matricellular protein CCN5 regulates podosome function via interaction with integrin αvβ3

Myers

Lan

Castellot

2014

J. Cell Commun. Signal.

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CCN proteins play crucial roles in cell motility, matrix turnover, and proliferation. In particular, CCN5 plays a role in cell motility and proliferation in several cell types; however, no functional binding proteins for CCN5 have been identified. In this study we report that CCN5 binds to the cell surface receptor integrin α v β 3 in vascular smooth muscle cells. Furthermore, this interaction takes place in podosomes, organelles known to degrade matrix and mediate motility. We show that CCN5 regulates the ability of podosomes to degrade matrix, but does not affect podosome formation. The level of CCN5 present in a podosome negatively correlates with its ability to degrade matrix. Conversely, knockdown of CCN5 greatly enhances the matrix-degrading ability of podosomes. These findings suggest that the antimotility effects of CCN5 may be mediated through the direct interaction of CCN5 and integrin α v β 3 in podosomes and the concomitant suppression of matrix degradation that is required for cell migration.

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Identification of a Novel Integrin αvβ3 Binding Site in CCN1 (CYR61) Critical for Pro-angiogenic Activities in Vascular Endothelial Cells

Cited by 121 publications

References 59 publications

CCN1: a novel target for pancreatic cancer

CCN1: a novel target for pancreatic cancer

Suppression of Cell Proliferation and Signaling Transduction by Connective Tissue Growth Factor in Non–Small Cell Lung Cancer Cells

The matricellular protein CCN5 regulates podosome function via interaction with integrin αvβ3

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