The Kindler Syndrome Protein Is Regulated by Transforming Growth Factor-β and Involved in Integrin-mediated Adhesion

Kloeker, Susanne; Major, Michael B.; Calderwood, David A.; Ginsberg, Mark H.; Jones, David A.; Beckerle, Mary C.

doi:10.1074/jbc.m307978200

Cited by 148 publications

(163 citation statements)

References 63 publications

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“…Therefore, it is plausible that in normal breast tissue, MIG2 is transcriptionally regulated by growth factors present in the dynamic, surrounding microenvironment, whereas in HMECs in culture, MIG2 is inducible only in response to growth factors present in the FBS. Results from several studies suggest that MIG2 can interact with other proteins such as integrin-linked kinase and hintegrins, both of which are important cell signaling molecules that have been implicated in oncogenesis (14,24,25). We have reported the expression of MIG2 in breast carcinomas and we present evidence for a role of MIG2 in the dynamic process of cancer cell invasion.…”

Section: Discussionmentioning

confidence: 63%

“…MIG2 belongs to a newly recognized protein family comprising URP1, URP2 and the Caenorhabditis elegans protein, UNC-112, which all share a unique protein structure consisting of two 4.1-ezrinradixin-moesin domains flanking a pleckstrin homology domain (13,14). MIG2 has been further characterized as a component of cell-ECM adhesion sites and described its involvement in controlling cell shape and spreading (15).…”

Section: Introductionmentioning

confidence: 99%

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Use of an Aggressive MCF-7 Cell Line Variant, TMX2-28, to Study Cell Invasion in Breast Cancer

Gozgit

Pentecost

Marconi

et al. 2006

Molecular Cancer Research

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An estrogen receptor -negative variant of the MCF-7 breast cancer cell line, TMX2-28, was used as a model in which to study breast cancer cell invasion. Using a reconstituted basement membrane (Matrigel) assay to evaluate cell invasion, we determined that TMX2-28 cells are more invasive than MCF-7 cells and that the invasiveness of TMX2-28 is similar to that of the aggressive MDA-MB-231 breast cancer cell line. TMX2-28 cells displayed a rounded, epithelial cell -like morphology, suggesting an amoeboid mode of cell invasion, in contrast to the mesenchymal mode of invasion characteristic of spindle-shaped, fibroblast-like MDA-MB-231 cells. Using real-time reverse transcription-PCR, we found that mitogen-inducible gene 2 (MIG2) is expressed at a 17-fold higher level in TMX2-28 cells than in nonaggressive MCF-7 cells and that MIG2 mRNA levels are low in the nontumorigenic human mammary epithelial cell line, 184. We determined that MIG2 plays a role in cell invasion by using small interfering RNA (siRNA) to suppress the expression of MIG2 mRNA levels in TMX2-28 cells. TMX2-28 cell invasion was reduced by 48% when the cells were transfected with siRNAs targeting MIG2, relative to cells transfected with siRNAs against glyceraldehyde-3-phosphate dehydrogenase. Finally, MIG2 expression was evaluated in reductive mammoplasty and breast tumor tissue. Although all 21 normal tissues from reduction mammoplasty showed immunoreactivity for MIG2, ranging from weak (62%) to strong (24%), only half of the 34 formalin-fixed breast tumors showed immunoreactivity for MIG2. Of these 17 positive cases, 10 were considered to overexpress MIG2 (moderate to strong staining). Examination of 30 frozen breast tumors supported the finding that MIG2 is overexpressed in a subset of breast cancers. We suggest that MIG2's normal regulation and function are disrupted in breast cancer. (Mol Cancer Res 2006;4(12):905 -13)

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Use of an Aggressive MCF-7 Cell Line Variant, TMX2-28, to Study Cell Invasion in Breast Cancer

Gozgit

Pentecost

Marconi

et al. 2006

Molecular Cancer Research

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“…The second and third hot-spots are the membrane distal NxxY and the membrane proximal NPxY motifs (Calderwood et al 2003). These second and third motifs bind to adaptor proteins that contain PTB domains, such as talin, kindlin 1, kindlin 2 and Shc (Calderwood et al 2002;Kloeker et al 2004;Shi et al 2007). The binding of talin to β-integrin tails via its structurally conserved PTB-like domain results in the separation of the α and β cytoplasmic tails and subsequent integrin activation (Wegener et al 2007;Wegener and Campbell 2008).…”

Section: Downstream Integrin Binding Partnersmentioning

confidence: 99%

Structural and mechanical functions of integrins

2013

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Integrins are ubiquitously expressed cell surface receptors that play a critical role in regulating the interaction between a cell and its microenvironment to control cell fate. These molecules are regulated either via their expression on the cell surface or through a unique bidirectional signalling mechanism. However, integrins are just the tip of the adhesome iceberg, initiating the assembly of a large range of adaptor and signalling proteins that mediate the structural and signalling functions of integrin. In this review, we summarise the structure of integrins and mechanisms by which integrin activation is controlled. The different adhesion structures formed by integrins are discussed, as well as the mechanical and structural roles integrins play during cell migration. As the function of integrin signalling can be quite varied based on cell type and context, an in depth understanding of these processes will aid our understanding of aberrant adhesion and migration, which is often associated with human pathologies such as cancer.

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“…The best studied examples are talin and kindlins, which are known to interact directly with cytoplasmic b1-and b3-domains and thus activate integrins through conformational changes (Tadokoro et al, 2003;Kloeker et al, 2004;Shi et al, 2007;Bouaouina et al, 2008). To test whether MDGI modulates integrin-mediated functions, we analyzed adhesion of multiple breast cancer cell lines (MDA-MB-468, MDA-MB-231, MCF-7 and SKBr-3) transiently or stably (polyclonal cell lines) expressing GFP and GFP-MDGI.…”

Section: Mdgi Expression Inhibits Adhesion Integrin Activity and Invmentioning

confidence: 99%

“…Separation of cytoplasmic a-and b-tails is associated with the final step in integrin activation, which is supported by binding of the talin head domain to the cytoplasmic btail (Anthis et al, 2009). However, talin binding alone may not be sufficient as members of the kindlin family interact with b-tails and cooperate with talin in integrin activation (reviewed in Kloeker et al, 2004;Shi et al, 2007;Bo¨ttcher et al, 2009). Different integrin conformations are important for cell motility, and activated integrins are present at the leading edge of migrating cells (Kiosses et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

et al. 2010

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The majority of mortality associated with cancer is due to formation of metastases from the primary tumor. Adhesion mediated by different integrin heterodimers has an important role during cell migration and invasion. Protein interactions with the b1-integrin cytoplasmic tail are known to influence integrin affinity for extracellular ligands, but regulating binding partners for the a-subunit cytoplasmic tails have remained elusive. In this study, we show that mammary-derived growth inhibitor (MDGI) (also known as FABP-3 or H-FABP) binds directly to the cytoplasmic tail of integrin a-subunits and its expression inhibits integrin activity. In breast cancer cell lines, MDGI expression correlates with suppression of the active conformation of integrins. This results in reduced integrin adhesion to type I collagen and fibronectin and inhibition of cell migration and invasion. In tissue microarray of 1331 breast cancer patients, patients with MDGI-positive tumors had more favorable 10-year distant disease-free survival compared with patients with MDGI-negative tumors. Our data indicate that MDGI is a novel interacting partner for integrin a-subunits, and its expression modulates integrin activity and suppresses cell invasion in breast cancer patients. Retained MDGI expression is associated with favorable prognosis.

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The Kindler Syndrome Protein Is Regulated by Transforming Growth Factor-β and Involved in Integrin-mediated Adhesion

Cited by 148 publications

References 63 publications

Use of an Aggressive MCF-7 Cell Line Variant, TMX2-28, to Study Cell Invasion in Breast Cancer

Use of an Aggressive MCF-7 Cell Line Variant, TMX2-28, to Study Cell Invasion in Breast Cancer

Structural and mechanical functions of integrins

Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

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