NORMAL GENOMIC

• Brown NH
• An integrin chicken and egg problem: which comes first, the extracellular matrix or the cytoskeleton?
• Curr Opin Cell Biol. 2000; 12: 629-33
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• Integrins have the ability to organise macromolecular structures both inside and outside the cell. Analysis of integrin function in the developing embryos of worms and flies suggests that, although the extracellular matrix directs integrins to organise intracellular proteins, the cytoskeleton may have the first word.

• Labat-Robert J, Robert L
• Interaction between cells and extracellular matrix: signaling by integrins and the elastin-laminin receptor.
• Prog Mol Subcell Biol. 2000; 25: 57-70

• Uhm JH, Gladson CL, Rao JS
• The role of integrins in the malignant phenotype of gliomas.
• Front Biosci. 1999; 4: 18899-18899
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• Integrins are cell surface receptors that mediate the physical and functional interactions between a cell and its surrounding extracellular matrix (ECM). Expressed as heterodimers, the specific alpha or beta chains that constitute the integrin receptor determine the repertoire of ECM proteins to which a specific integrin may bind (table 1). While classically, the role ascribed to integrins has been that of anchoring cells to the ECM, the more contemporary spectrum of integrin function greatly exceeds that of mere cell adhesion. Recent reports have demonstrated that the interaction between the ECM and cell surface integrins leads to intracellular signaling events that affect cell migration, proliferation, and survival, which in the context of neoplastic cells, can translate directly into the malignant phenotype (1). Indeed, the role of specific integrins in tumorigenesis has been demonstrated in numerous cancer types (table 2). In primary tumors of the nervous system, the contribution of integrins to the malignant phenotype of gliomas has been an area of significant attention and research in numerous laboratories, including that of ours. As illustrated in table 3, several integrins have been identified as being of key importance in glioma biology. In this article, we review the current knowledge of how these integrins influence the malignant characteristics of gliomas and, as such, how these cell surface receptors may thus represent potential targets in the design of future therapeutics for patients afflicted with gliomas.

• Streuli CH, Gilmore AP
• Adhesion-mediated signaling in the regulation of mammary epithelial cell survival.
• J Mammary Gland Biol Neoplasia. 1999; 4: 183-91
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• Tissue architecture in multicellular organisms is maintained through adhesive interactions between cells and their neighbors, and between cells and the underlying extracellular matrix. These interactions are important in the dynamic regulation of tissue organization as well as the control of cell proliferation, differentiation and apoptosis. The ultimate goal of this regulation is to promote cell growth and differentiation only when the cell is in the correct location, and to delete cells that have become displaced from their proper environment. It therefore plays an important role in development and tissue remodeling. In this review we consider the molecular mechanisms by which cell-matrix interactions contribute to cell survival, and discuss their role in mammary gland development and function.

• Palecek SP, Horwitz AF, Lauffenburger DA
• Kinetic model for integrin-mediated adhesion release during cell migration.
• Ann Biomed Eng. 1999; 27: 219-35
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• Under many circumstances, cell migration speed is limited by the rate of cell-substratum detachment at the cell rear. We have constructed a mathematical model to integrate how the biophysical and biochemical interactions between integrins, the cytoskeleton, and the matrix affect rear retraction and linkage dissociation mechanisms. Our model also examines how applied forces and integrin clustering affect retraction kinetics. The model predicts two distinct detachment phenotypes. In the first, detachment is extremely rapid, dominated by integrin extracellular-matrix dissociation, and it occurs at high forces or low adhesiveness. In the second, detachment is much slower, dominated by integrin-cytoskeleton dissociation, and it occurs at low forces or high adhesiveness. The amount of integrin extracted from the rear of the cell is an assay for the detachment phenotype. During rapid detachment cells leave little integrin on the substratum whereas during slow detachment a large fraction of integrin rips from the membrane. This model delineates parameters which can be exploited to regulate cell speed in each detachment regime. The model also offers an explanation as to why some cell types, such as leukocytes or keratocytes, are able to detach easily and move very quickly while other cell types, such as fibroblasts, tend to migrate more slowly and release many more integrins during detachment.

• Svoboda KK
• Chondrocyte-matrix attachment complexes mediate survival and differentiation.
• Microsc Res Tech. 1998; 43: 111-22
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• Integrin mediated cell-extracellular matrix interactions are required for survival and differentiation of many cell types. In this review, the cell-matrix attachment complex (CMAX) is described for chondrocytes. The evidence that integrin-mediated signal transduction is necessary for normal chondrocyte differentiation and survival in various culture conditions and in vivo are reviewed. The possible signal transduction pathways stimulated by the extracellular matrix components are discussed with a review of current data from chondrocyte experiments. In addition, the influence of parathyroid hormone and transforming growth factor beta on chondrocyte survival has been included as they may function in concert with integrin mediated signal transduction. Finally, specific changes in gene expression preceding apoptosis are discussed. The current understanding of how integrin-mediated signals prevent apoptosis and implications of anchorage-dependent survival for development and differentiation of the chondrocyte phenotype are discussed.

• Green LJ, Mould AP, Humphries MJ
• The integrin beta subunit.
• Int J Biochem Cell Biol. 1998; 30: 179-84
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• The integrin family of cell adhesion receptors plays a fundamental role in the processes involved in cell division, differentiation and movement. The extracellular domains of integrin alpha/beta heterodimers mediate cell-matrix and cell-cell contacts while their cytoplasmic tails associate with the cytoskeleton. Integrins are capable of transducing information in a bidirectional manner and the beta subunit is now recognised to play an important role in this process. Recent studies have led to the identification of a ligand-binding region on the beta subunit similar to that already characterised on some alpha subunits, and sequences in the cytoplasmic tails of the beta subunits that interact with cytoskeletal and signalling components. Adhesive events can also play a role in the progression of all four major classes of human disease--neoplastic, inflammatory, traumatic and infectious--and the specific nature of integrin adhesion mechanisms make them an attractive target for therapy.

• Hirsch MS, Lunsford LE, Trinkaus-Randall V, Svoboda KK
• Chondrocyte survival and differentiation in situ are integrin mediated.
• Dev Dyn. 1997; 210: 249-63
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• Chondrocytes in specific areas of the chick sternum have different developmental fates. Cephalic chondrocytes become hypertrophic and secrete type X collagen into the extracellular matrix prior to bone deposition. Middle and caudal chondrocytes remain cartilaginous throughout development and continue to secrete collagen types II, IX, and XI. The interaction of integrin receptors with extracellular matrix molecules has been shown to affect cytoskeleton organization, proliferation, differentiation, and gene expression in other cell types. We hypothesized that chondrocyte survival and differentiation including the deposition into interstitial matrix of type X collagen may be integrin receptor mediated. To test this hypothesis, a serum-free organ culture sternal model that recapitulates normal development and maintains the three-dimensional relationships of the tissue was developed. We examined chondrocyte differentiation by five parameters: type X collagen deposition into interstitial matrix, sternal growth, actin distribution, cell shape, and cell diameter changes. Additional sterna were analyzed for apoptosis using a fragmented DNA assay. Sterna were organ cultured with blocking antibodies specific for integrin subunits (alpha2, alpha3, or beta1). In the presence of anti-beta1 integrin (25 microg/ml, clone W1B10), type X collagen deposition into interstitial matrix and sternal growth were significantly inhibited. In addition, all chondrocytes were significantly smaller, the actin was disrupted, and there was a significant increase in apoptosis throughout the specimens. Addition of anti-alpha2 (10 microg/ml, clone P1E6) or anti-alpha3 (10 microg/ml, clone P1B5) integrin partially inhibited type X collagen deposition into interstitial matrix; however, sternal growth and cell size were significantly decreased. These data are the first obtained from intact tissue and demonstrate that the interaction of chondrocytes with extracellular matrix is required for chondrocyte survival and differentiation.

• Hirsch MS, Svoboda KK
• Beta 1 integrin antibodies inhibit chondrocyte terminal differentiation in whole sterna.
• Ann N Y Acad Sci. 1996; 785: 267-70

• Borradori L, Sonnenberg A
• Hemidesmosomes: roles in adhesion, signaling and human diseases.
• Curr Opin Cell Biol. 1996; 8: 647-56
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• Our understanding of the role of hemidesmosomes in cell-substratum adhesion has greatly improved both as a result of targeted gene mutation experiments and by means of observations of several blistering disorders of the skin in which the absence or defects of hemidesmosomal proteins have been demonstrated. Functionally important domains within the proteins that constitute hemidesmosomes have recently been identified by transfection and mutagenesis studies. These multiprotein complexes appear not only to mediate cell adhesion, but also to transduce signals from the extracellular matrix to the cell interior that may profoundly modulate cell behavior.

• Marshall JF, Hart IR
• The role of alpha v-integrins in tumour progression and metastasis.
• Semin Cancer Biol. 1996; 7: 129-38
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• Metastatic tumour spread is a pathologic process which can be described as altered cell growth associated with a series of adhesion/de-adhesion events which are coupled with regulated tissue degradation. Adhesion to, and migration through, the extracellular matrix (ECM) is necessary for the tumour invasion which is an important part of the metastatic process. Efficient proteolytic digestion of the molecules of the ECM appears to be facilitated by the localization of proteases at the cell surface-tissue interface (see also review by Stetler-Stevenson). Indeed, there is evidence from in-vitro studies to suggest that restriction of these enzymes to focal contact sites (areas of cell-substratum contact) may occur and that this sub-cellular juxtaposition of receptors and enzymes co-ordinates regulation of adhesion and proteolysis by the neoplastic cells. How such co-ordinated regulation is achieved and how this dynamic interplay is controlled during tumour development and progression are important areas of investigation.

• Birchmeier C, Birchmeier W
• Molecular aspects of mesenchymal-epithelial interactions.
• Annu Rev Cell Biol. 1993; 9: 511-40