The α6β4 Integrin Maintains the Survival of Human Breast Carcinoma Cells <i>In vivo</i>

Lipscomb, Elizabeth A.; Simpson, Kaylene J.; Lyle, Stephen; Ring, Jennifer E.; Dugan, Aisling S.; Mercurio, Arthur M.

doi:10.1158/0008-5472.can-05-2327

Cited by 92 publications

(89 citation statements)

References 32 publications

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“…In contrast, the a 6 b 4 integrin complex is overexpressed in the majority of PDAC cell lines in vitro (data not shown) and pancreatic cancers tissues in vivo (Gleason et al, 2005). The functional role of a 6 b 4 is correlated with its ability to promote the migration and survival of carcinoma cells via activation of the PI3 kinase pathway and is both dependent and independent on its interaction with laminin substrates (Lipscomb and Mercurio, 2005). Therefore, the observation that periostin promotes phosphorylation of AKT after binding to a 6 b 4 and activation of the PI3 kinase pathway is well correlated with the role of this integrin receptor in metastatic spread of carcinoma cells.…”

Section: Discussionmentioning

confidence: 92%

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Baril¹,

Gangeswaran²,

Mahon³

et al. 2006

Oncogene

257

244

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Pancreatic ductal adenocarcinoma is a devastating disease, characterized by a rapid progression and poor treatment response. Using gene expression profiling of pancreatic cancer tissues, we previously identified periostin as a potential diagnostic and therapeutic target. In this study, we report the overexpression of periostin in a larger set of pancreatic cancer tissues and show that although the periostin transcript is exclusively expressed in tumour cells, the protein product is only detected in the extracellular matrix adjacent to cancer cells. Using an enzyme-linked immunosorbent assay (ELISA) assay, we show significantly increased levels of periostin in the sera of pancreatic cancer patients compared to non-cancer controls. We demonstrate that periostin promotes the invasiveness of tumour cells by increasing the motility of cells without inducing expression of proteases, and enhances the survival of tumour cells exposed to hypoxic conditions. At the molecular level, we provide evidence that the a 6 b 4 integrin complex acts as the cell receptor of periostin in pancreatic cancer cells and that interaction promotes phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) though activation of the PI3 kinase pathway, but not the RAS/MEK/ERK pathway. These findings suggest an important role of periostin in pancreatic cancer and provide a rationale to study periostin for diagnostic and therapeutic applications.

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Section: Discussionmentioning

confidence: 92%

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Baril¹,

Gangeswaran²,

Mahon³

et al. 2006

Oncogene

257

244

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“…Activation of ␣6␤4 integrin signaling in tumor cells deficient in p53, such as the A431 cells, provides protection from apoptosis by activating Akt (3,22,24). We found that silencing endogenous Sdc1 expression in the A431 cells caused an 8-fold increase in apoptosis (to nearly 50% of the cells) after 55 h, as assessed by fluorescent Annexin V staining (Fig.…”

Section: Resultsmentioning

confidence: 71%

Interaction of Syndecan and α6β4 Integrin Cytoplasmic Domains

Wang

Leavitt

Ramaswamy

et al. 2010

Journal of Biological Chemistry

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The ␣6␤4 integrin is a laminin 332 (LN332) receptor central to the formation of hemidesmosomes in epithelial layers. However, the integrin becomes phosphorylated by keratinocytes responding to epidermal growth factor in skin wounds or by squamous cell carcinomas that overexpress/hyperactivate the tyrosine kinase ErbB2, epidermal growth factor receptor, or c-Met. We show here that the ␤4-dependent signaling in A431 human squamous carcinoma cells is dependent on the syndecan family of matrix receptors. Yeast two-hybrid analysis identifies an interaction within the distal third (amino acids 1473-1752) of the ␤4 cytoplasmic domain and the conserved C2 region of the syndecan cytoplasmic domain. Via its C2 region, Sdc1 forms a complex with the ␣6␤4 integrin along with the receptor tyrosine kinase ErbB2 and the cytoplasmic kinase Fyn in A431 cells. Engagement of LN332 or clustering of the ␣6␤4 integrin with integrin-specific antibodies causes phosphorylation of ErbB2, Fyn, and the ␤4 subunit as well as activation of phosphatidylinositol 3-kinase and Akt and their assimilation into this complex. This leads to phosphatidylinositol 3-kinase-dependent cell spreading and Akt-dependent protection from apoptosis. This is disrupted by RNA interference silencing of Sdc1 but can be rescued by mouse Sdc1 or Sdc4 but not by syndecan mutants lacking their C-terminal C2 region. This disruption does not prevent the phosphorylation of ErbB2 or Fyn but blocks the Fynmediated phosphorylation of the ␤4 tail. We propose that syndecans engage the distal region of the ␤4 cytoplasmic domain and bring it to the plasma membrane, where it can be acted upon by Src family kinases.The ␣6␤4 integrin is a laminin 332 (LN332, 2 also known as LN5 or kalinin) receptor that forms hemidesmosomes in epithelial cells (reviewed in Refs. 1-4). It engages LN332 linked to collagen VII anchoring fibrils in the extracellular matrix (5) and simultaneously engages cytoplasmic proteins (e.g. plectin and BP230) and the transmembrane protein BP180 via the long (ϳ1,000-amino acid) cytoplasmic domain of the ␤4 integrin subunit. These cytoplasmic interactions involve two pairs of fibronectin type III (FNIII) repeats in the ␤4 tail and the connecting segment joining these pairs. This couples the integrin to the intermediate filament cytoskeleton and provides a stable anchorage that resists frictional forces on the epithelium.In contrast to this stabilizing role of the ␣6␤4 integrin, phosphorylation of the ␤4 cytoplasmic domain causes hemidesmosome disassembly and activation of ␣6␤4 signaling. Skin wounding causes relocalization of the integrin to lamellipodia of invading keratinocytes in response to EGF or macrophagestimulating factor (6). In tumor cells, overexpression of the integrin or overexpression and/or hyperactivation of the receptor tyrosine kinase c-Met (hepatocyte growth factor receptor), ErbB1 (EGFR), or ErbB2 causes phosphorylation of the integrin and promotes the proliferation, survival, and invasion of the tumor cells (7-9). The sites targeted by these kin...

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“…Its expression is up-regulated in colorectal cancer (42) presumably due in part to ZKSCAN3 as we have shown herein. Integrin ␤4 has recently emerged as a mediator of cancer development and tumor progression (22,43,44), albeit in skin and breast cancer, and may function as a "servo" oncogene (43) by virtue of its ability to co-opt diverse receptor tyrosine kinases (30,31) and phosphatidyl 3-kinase signaling downstream (37). In fact, the ability of integrin ␤4 to intersect with phosphatidyl 3-kinase signaling is notable considering the recent implication of the latter in driving colorectal cancer progression (9,45).…”

Section: Discussionmentioning

confidence: 99%

“…expressing HCT 116 cells were transduced with a retrovirus bearing an integrin ␤4-targeting shRNA (22). Expectedly, although ZKSCAN3 induced integrin ␤4 mRNA levels (Fig.…”

Section: Volume 283 • Number 50 • December 12 2008mentioning

confidence: 92%

“…1, B and C) was intriguing because this protein has been implicated in tumorigenicity (22,35) and cell migration (36). Moreover, integrin ␤4 stimulates the phosphatidyl 3-kinase (PI3K) signaling module (37) implicated in colorectal cancer progression (9), and indeed increased phosphorylated Akt levels (Fig.…”

Section: Identification Of a Dna Binding Site For Zkscan3 By Cyclicmentioning

confidence: 99%

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Unbiased Screening for Transcriptional Targets of ZKSCAN3 Identifies Integrin β4 and Vascular Endothelial Growth Factor as Downstream Targets

Yang

Zhang

et al. 2008

Journal of Biological Chemistry

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We previously described the novel zinc finger protein ZKSCAN3 as a new "driver" of colon cancer progression. To investigate the underlying mechanism and because the predicted structural features (tandem zinc fingers) are often present in transcription factors, we hypothesized that ZKSCAN3 regulates the expression of a gene(s) favoring tumor progression. We employed unbiased screening to identify a DNA binding motif and candidate downstream genes. Cyclic amplification and selection of targets using a random oligonucleotide library and ZKSCAN3 protein identified KRDGGG as the DNA recognition motif. In expression profiling, 204 genes were induced 2-29-fold, and 76 genes reduced 2-5-fold by ZKSCAN3. To enrich for direct targets, we eliminated genes under-represented (<3) for the ZKSCAN3 binding motif (identified by CAST-ing) in 2 kilobases of regulatory sequence. Up-regulated putative downstream targets included genes contributing to growth (c-Metrelated tyrosine kinase (MST1R), MEK2; the guanine nucleotide exchanger RasGRP2, insulin-like growth factor-2, integrin ␤4), cell migration (MST1R), angiogenesis (vascular endothelial growth factor), and proteolysis (MMP26; cathepsin D; PRSS3 (protease serine 3)). We pursued integrin ␤4 (induced up to 6-fold) as a candidate target because it promotes breast cancer tumorigenicity and stimulates phosphatidyl 3-kinase implicated in colorectal cancer progression. ZKSCAN3 overexpression/silencing modulated integrin ␤4 expression, confirming the array analysis. Moreover, ZKSCAN3 bound to the integrin ␤4 promoter in vitro and in vivo, and the integrin ␤4-derived ZKSCAN3 motif fused upstream of a tk-Luc reporter conferred ZKSCAN3 sensitivity. Integrin ␤4 knockdown by short hairpin RNA countered ZKSCAN3-augmented anchorage-independent colony formation. We also demonstrate vascular endothelial growth factor as a direct ZKSCAN3 target. Thus, ZKSCAN3 regulates the expression of several genes favoring tumor progression including integrin ␤4.

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The α6β4 Integrin Maintains the Survival of Human Breast Carcinoma Cells In vivo

Cited by 92 publications

References 32 publications

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Interaction of Syndecan and α6β4 Integrin Cytoplasmic Domains

Unbiased Screening for Transcriptional Targets of ZKSCAN3 Identifies Integrin β4 and Vascular Endothelial Growth Factor as Downstream Targets

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