Role of the Focal Adhesion Protein Kindlin-1 in Breast Cancer Growth and Lung Metastasis

Sin, Soraya; Bonin, Florian; Petit, Valérie; Meseure, Didier; Lallemand, François; Bièche, Ivan; Bellahcène, Akeila; Castronovo, Vincent; Wever, Olivier De; Gespach, Christian; Lidereau, Rosette; Driouch, Keltouma

doi:10.1093/jnci/djr290

Cited by 73 publications

(88 citation statements)

References 59 publications

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“…Kindlin-3 is expressed primarily in white blood cells; its loss of function is associated with leukocyte attachment deficiency (LAD) (38). Overexpression of Kindlins has been detected frequently in human cancers (39)(40)(41). We focused on the function of kindlin-2 in fibroblasts, as they control the production of many extracellular matrix proteins.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

You

et al. 2016

Molecular and Cellular Biology

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c RNA polymerase I-mediated rRNA production is a key determinant of cell growth. Despite extensive studies, the signaling pathways that control RNA polymerase I-mediated rRNA production are not well understood. Here we provide original evidence showing that RNA polymerase I transcriptional activity is tightly controlled by integrin signaling. Furthermore, we show that a signaling axis consisting of focal adhesion kinase (FAK), Src, phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR mediates the effect of integrin signaling on rRNA transcription. Additionally, we show that in kindlin-2 knockout mouse embryonic fibroblasts, overactivation of Ras, Akt, and Src can successfully rescue the defective RNA polymerase I activity induced by the loss of kindlin-2. Finally, through experiments with inhibitors of FAK, Src, and PI3K and rescue experiments in MEFs, we found that the FAK/Src/PI3K/Akt signaling pathway to control rRNA transcription is linear. Collectively, these studies reveal, for the first time, a pivotal role of integrin signaling in regulation of RNA polymerase I transcriptional activity and shed light on the downstream signaling axis that participates in regulation of this key aspect of cell growth. RNA polymerase I (Pol I) plays a central role in regulating cellular growth and proliferation (1). Eukaryotic cells contain hundreds of ribosomal DNA (rDNA) copies that occupy several different chromosomal locations (2). The production of rRNA can be divided into several steps, i.e., rRNA transcription, modification, and processing, all of which occur in the nucleolus (3, 4). The rate-limiting step is rRNA transcription (1, 5). On sensing of outside stimuli, a preinitiation complex comprised of the transcriptional factors upstream binding factor (UBF), SL1, TBP, Rrn3, and TTF assembles in the promoter region of rDNA. This complex then recruits RNA polymerase I to rDNA loci, and rRNA transcription starts (6-8). In mammalian cells, a single precursor rRNA transcript, 47S rRNA (14.3 kb), is transcribed from rDNA by the RNA polymerase I complex. This large polycistronic transcript encompasses 18S, 5.8S, and 28S rRNAs and includes several spacer regions, which are later processed into distinct rRNA species before assembly into preribosomal subunits (9).The transcriptional activity of Pol I is a fundamental determinant of cell proliferation capacity (3). In rapidly proliferating cells, rRNA production takes more than 50% of all nuclear transcriptional activity. In yeast cells, this percentage can reach more than 80% (10). As such, the tremendous energy consumption demands tight control.At the tissue level, cells attach to the extracellular matrix (ECM) through cell surface receptors termed integrins (11). Integrins are heterodimeric transmembrane receptors comprised of ␣ subunits and ␤ subunits that bind to extracellular ligands, such as laminin, collagen, vitronectin, and fibronectin. Different combinations of the 18 ␣ subunits and 8 ␤ subunits confer specificity on the integrin-ECM interactions (12). After binding ...

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Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

You

et al. 2016

Molecular and Cellular Biology

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“…The consequence in disease situations -such as in KS that lacks kindlin-1, or in cancer cells that present with high levels of αvβ6 integrin and low levels of kindlin-1 (see below; Rognoni et al, 2014;Sin et al, 2011) -is the inability of kindlin-2 to compensate for loss of kindlin-1 and, hence, to activate αvβ6 integrin. The differential binding specificities of kindlin-1 and -2 for αvβ6 integrins are due to evolutionary splitting of the kindlin family, allowing specific regulation of tissue-specific integrin classes and associated signaling pathways, and even differential regulation of integrins when multiple integrin isoforms are expressed in a cell.…”

Section: Subcellular Localisations Of Kindlinsmentioning

confidence: 99%

“…Although kindlin-1 appears to have a tumor suppressor function in cutaneous epithelial cells, KINDLIN-1 mRNA levels are increased in the majority of lung, breast and colon cancers (Sin et al, 2011;Weinstein et al, 2003), and in several pancreatic cancer cell lines, where it promotes carcinogenesis by inducing migration and invasion (Mahawithitwong et al, 2013a) (Table 1). In these cancers, kindlin-1 exerts an oncogenic effect that appears to be strongly dependent on TGFβ signaling (Sin et al, 2011).…”

Section: Kindlin-1 Kindlin-2 Kindlin-3mentioning

confidence: 99%

The kindlin family: functions, signaling properties and implications for human disease

Rognoni

Ruppert

Fässler

2016

Journal of Cell Science

191

186

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The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation.

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“…BMP and WNT signaling can regulate EMT (Lim and Thiery, 2012;Micalizzi and Ford, 2009), and both are involved in NNE, NE and NCC specification (Steventon et al, 2005). Fermitin family homolog 1 (FERMT1, also known as kindlin-1) is a focal adhesion protein involved in integrin activation, adhesion of keratinocytes to fibronectin and laminin, wound healing, and EMT regulation in breast cancer cells, and FERMT1 mutations result in Kindler syndrome, which is characterized by skin blistering (Larjava et al, 2008;Siegel et al, 2003;Ussar et al, 2008;Sin et al, 2011). Tripartite motif-containing 29 (TRIM29, also known as ATDC) is tumor promoting or suppressive depending on the context, and acts as an EMT suppressor in breast cancer (Ai et al, 2014;Liu et al, 2012).…”

Section: Wild-type Nne Expresses Potential Emt Suppressorsmentioning

confidence: 99%

Grainyhead-like 2 downstream targets act to suppress EMT during neural tube closure

Ray

Niswander

2016

Development

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The transcription factor grainyhead-like 2 (GRHL2) is expressed in non-neural ectoderm (NNE) and Grhl2 loss results in fully penetrant cranial neural tube defects (NTDs) in mice. GRHL2 activates expression of several epithelial genes; however, additional molecular targets and functional processes regulated by GRHL2 in the NNE remain to be determined, as well as the underlying cause of the NTDs in Grhl2 mutants. Here, we find that Grhl2 loss results in abnormal mesenchymal phenotypes in the NNE, including aberrant vimentin expression and increased cellular dynamics that affects the NNE and neural crest cells. The resulting loss of NNE integrity contributes to an inability of the cranial neural folds to move toward the midline and results in NTD. Further, we identified Esrp1, Sostdc1, Fermt1, Tmprss2 and Lamc2 as novel NNE-expressed genes that are downregulated in Grhl2 mutants. Our in vitro assays show that they act as suppressors of the epithelial-to-mesenchymal transition (EMT). Thus, GRHL2 promotes the epithelial nature of the NNE during the dynamic events of neural tube formation by both activating key epithelial genes and actively suppressing EMT through novel downstream EMT suppressors.

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Role of the Focal Adhesion Protein Kindlin-1 in Breast Cancer Growth and Lung Metastasis

Abstract: These results suggest a role for kindlin-1 in breast cancer lung metastasis and lung tumorigenesis and advance our understanding of kindlin-1 as a regulator of TGFβ signaling, offering new avenues for therapeutic intervention against cancer progression.

Cited by 73 publications

References 59 publications

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

The kindlin family: functions, signaling properties and implications for human disease

Grainyhead-like 2 downstream targets act to suppress EMT during neural tube closure

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