An RGD Motif Present in Cadherin 17 Induces Integrin Activation and Tumor Growth

Bartolomé, Rubén A.; Peláez‐García, Alberto; Gómez, Inmaculada Postigo; Torres, Sofía; Fernández-Aceñero, M. Jesús; Escudero-Paniagua, Beatriz; Imbaud, Juan I.; Casal, J. Ignacio

doi:10.1074/jbc.m114.600502

Cited by 40 publications

(65 citation statements)

References 29 publications

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“…Stiff substrates enhanced colorectal cancer cell viability by upregulating MMP-7 expression through a positive feedback loop containing YAP, EGFR, integrin-α2β1 and MRLC, independent of Hippo pathway [25]. α2β1 integrin can directly interact with CDH17 through its RGD motif [44], which causes β1 integrin activation and signaling to induce focal adhesion kinase and Ras activation, leading to colorectal cancer cells proliferation and liver metastasis [28]. Despite these important findings, the cell-surface components upstream the Hippo pathway and that sense the pathway to extracellular stimuli, especially in the context of pathogenesis like carcinogenesis, have remained to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma

et al. 2016

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The Hippo pathway regulates the down-stream target Yes-associated protein (YAP) to maintain organ homeostasis, which is commonly inactivated in many types of cancers. However, how cell adhesion dysregulates the Hippo pathway activating YAP oncogene in hepatocellular carcinoma (HCC) remains unclear. Our findings demonstrate that α2β1 integrin (but not other β1 integrins) expressed in HCC cells, after binding to collagen extracellular matrix, could inhibit MST1 kinase phosphorylation and activate YAP pro-oncogenic activities. Knockdown of integrin α2 gene (ITGA2) suppressed YAP targeted gene expression in vitro. α2β1 and collagen binding resulted in suppressing Hippo signaling of mammalian sterile 20-like kinase 1 (MST1) and Large tumor suppressor homolog 1 (LATS1) with concomitant activation of YAP-mediated connective tissue growth factor (CTGF) gene expression. In vitro kinase assay showed that MST1 is an immediate downstream target of integrin α2 with S1180 residue as the critical phosphorylation site. Clinical correlational analysis using a gene expression dataset of 228 HCC tumors revealed that ITGA2 expression was significantly associated with tumor progression, and co-expression with YAP targeted genes (AXL receptor tyrosine kinase, CTGF, cyclin D1, glypican 3, insulin like growth factor 1 receptor, and SRY-box 4) correlated with survivals of HCC patients. In conclusion, α2β1 integrin activation through cellular adhesion impacts the Hippo pathway in solid tumors and modulates MST1-YAP signaling cascade. Targeting integrin α2 holds promises for treating YAP-positive HCC.

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Section: Discussionmentioning

confidence: 99%

Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma

et al. 2016

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“…Particularly, adhesion, proliferation, invasion, and metastasis of colon cancer on collagen type I and IV and cadherin 17 were promoted through FAK‐mediated extracellular signal‐regulated kinase (ERK) activation (see Supporting Information Tables S3 and S4). Thus, same as collagen type I, it seems that induction of HT29 CSLCs on keratin substrate is mediated by FAK–ERK signaling pathway.…”

Section: Discussionmentioning

confidence: 93%

“…It is well known that α 2 β 1 heterodimer has two different receptors sites. The I domain of α 2 subunit can interact with GFOGER motif on ligands such as collagen type I and IV, while the β‐subunit I‐like domain of α2β1 integrin mediates the attachment to RGD motif on different ligands such as cadherins 17 and 6 . Keratin molecules contain receptor binding motifs such as LDV and RGD that mediate cellular adhesion .…”

Section: Discussionmentioning

confidence: 99%

Using of keratin substrate for enrichment of HT29 colorectal cancer stem‐like cells

et al. 2018

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Eradication of cancer stem-like cells (CSLCs) are becoming increasingly an important target for new cancer therapies. The ability to study their behavior in vitro will provide the opportunity for high-throughput testing of more effective treatments. In this study, spheroid-like structures' formation and enrichment of HT29 CSLCs were evaluated on a wool keratin-based substrate as a bio-mimic of natural extracellular matrix (ECM) proteins. The results indicated that culturing on keratin substrate increased spheroid formation ability and radio-/chemoresistance of HT29 cells. Moreover, cell surface expression of CD133 CSLCs' marker and the mRNA level of stemness genes such as Nanog, Oct4, and c-MYC were increased. These data suggest that keratin can potentially be used for spheroid-like structure formation and enrichment of HT29 CSLCs. In addition, it seems that the induction of stemness characteristics on keratin substrate is probably because of the activation of α 2 β 1 integrin signaling pathway.

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“…For instance, the shedding events of the proteins CDH1, EFNA1, and SDC1 were suggested to be involved in cancer invasion and immune escape [16][17][18][19][20]; the shedding events of SNCA and APP were shown to be involved in neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease [21][22][23]; the shedding event of NRP2 was involved in immune disorders such as rheumatoid arthritis [24]; that of SDC4 was suggested to be involved in cardiovascular diseases such as atrial fibrillation [25]; HAVCR2 shedding event being implicated in HIV infection [26]; and the shedding event of CADM1 was shown to be involved in diabetes [27,28]. In addition, several shed or soluble membrane proteins were suggested to be marker candidates for cancers (e.g., PVRL4 [29], CD200 [30,31], CDH17 [32]), atherosclerosis (e.g., SORL1 [33][34][35][36]), diabetes mellitus (e.g., CLEC1B [37]), neurodegenerative disorders (e.g., PDGFRB [38,39]), and hepatocyte damage (e.g., PTPRG [40]).…”

Section: Database Contentmentioning

confidence: 99%

SheddomeDB: the ectodomain shedding database for membrane-bound shed markers

Tien

Chen

2017

BMC Bioinformatics

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BackgroundA number of membrane-anchored proteins are known to be released from cell surface via ectodomain shedding. The cleavage and release of membrane proteins has been shown to modulate various cellular processes and disease pathologies. Numerous studies revealed that cell membrane molecules of diverse functional groups are subjected to proteolytic cleavage, and the released soluble form of proteins may modulate various signaling processes. Therefore, in addition to the secreted protein markers that undergo secretion through the secretory pathway, the shed membrane proteins may comprise an additional resource of noninvasive and accessible biomarkers. In this context, identifying the membrane-bound proteins that will be shed has become important in the discovery of clinically noninvasive biomarkers. Nevertheless, a data repository for biological and clinical researchers to review the shedding information, which is experimentally validated, for membrane-bound protein shed markers is still lacking.ResultsIn this study, the database SheddomeDB was developed to integrate publicly available data of the shed membrane proteins. A comprehensive literature survey was performed to collect the membrane proteins that were verified to be cleaved or released in the supernatant by immunological-based validation experiments. From 436 studies on shedding, 401 validated shed membrane proteins were included, among which 199 shed membrane proteins have not been annotated or validated yet by existing cleavage databases. SheddomeDB attempted to provide a comprehensive shedding report, including the regulation of shedding machinery and the related function or diseases involved in the shedding events. In addition, our published tool ShedP was embedded into SheddomeDB to support researchers for predicting the shedding event on unknown or unrecorded membrane proteins.ConclusionsTo the best of our knowledge, SheddomeDB is the first database for the identification of experimentally validated shed membrane proteins and currently may provide the most number of membrane proteins for reviewing the shedding information. The database included membrane-bound shed markers associated with numerous cellular processes and diseases, and some of these markers are potential novel markers because they are not annotated or validated yet in other databases. SheddomeDB may provide a useful resource for discovering membrane-bound shed markers. The interactive web of SheddomeDB is publicly available at http://bal.ym.edu.tw/SheddomeDB/.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-017-1465-7) contains supplementary material, which is available to authorized users.

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An RGD Motif Present in Cadherin 17 Induces Integrin Activation and Tumor Growth

Cited by 40 publications

References 29 publications

Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma

Integrin α2β1 inhibits MST1 kinase phosphorylation and activates Yes-associated protein oncogenic signaling in hepatocellular carcinoma

Using of keratin substrate for enrichment of HT29 colorectal cancer stem‐like cells

SheddomeDB: the ectodomain shedding database for membrane-bound shed markers

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