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A laminin-rich basement membrane BM is of particular importance as it orients the polarity of epithelial cells by serving as a ligand for members of the integrin family of ECM receptors. Twenty-four different integrin heterodimers have been reported in humans. How the different integrins convey signals from the ECM into the cells is not thoroughly understood.

However, it is clear that even subtle dysfunctions in this reciprocal communication can disrupt organ functionality.

Therefore, it is important to build up comprehensive knowledge of the regulation of epithelial cell function by cell—ECM interactions. Dissecting the functional roles of specific integrins in epithelial cells The bi-directional function of integrins enables ECM binding by the cell while simultaneously sensing its chemical composition and physical properties. Sites of integrin adhesion serve as localized organizing centres for the cytoskeleton, regulating changes in the cell architecture.

Integrin adhesion sites are also sensitive to mechanical stimuli and capable of imparting contractility across the cytoskeleton, thereby facilitating processes such as cell spreading and migration. A clear link exists between integrin functions, cell polarity and epithelial morphogenesis. Moreover, integrins are central to development as well as to epithelial pathologies, but their specific roles at a cellular level as well as molecular machineries underlying their specific functions have not been thoroughly characterized.

It is evident that even integrins with similar ligands have differing cellular functions governed via mechanisms beyond their ligand-binding specificity. A complex network of accompanying effector molecules at the cell membrane fine-tunes the cellular response. By utilizing comprehensive analysis of integrin associated complexes IACs we investigate the protein-protein interaction networks that exert the functions of specific integrins. Integrin-mediated signals in the regulation of epithelial cell shape and morphogenesis In three-dimensional 3D culture environments MDCK cells recapitulate epithelial morphogenesis by forming polarized lumen-enclosing spherical cysts.

In our ongoing studies we are addressing the molecular mechanisms by which integrins transmit BM-derived signals to regulate epithelial cell polarization and morphogenesis.

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To better understand the molecular mechanisms underlining these phenomena, we isolate IACs from different integrin-mutant cell lines and employ a mass spectrometry-based approaches to identify critical IAC-components that mediate specific functions of BM-binding integrins. Integrins lack enzymatic activity, so they rely on associated proteins which modulate cellular signal transduction pathways and thereby cellular functions. Specific integrin functions in prostate cancer In several tumour types, the regulation of integrin-mediated signalling is perturbed, thereby contributing to abnormal migration, invasion, proliferation and survival of tumour cells.

Although integrins themselves are not thought to transform cells, recent data demonstrate that several integrins contribute to tumorigenesis by inhibiting or cooperating with oncogenes. The vast majority of diagnosed cancers are carcinomas that originate from epithelium of skin, breast, prostate, colon or kidneys.

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In this project we study functional synergies or antagonisms between selected integrins implicated in the regulation of epithelial polarity in our previous studies with prostate cancer associated oncogenes and loss of tumour suppressors. Our aim is to facilitate the development of novel targeted therapeutic approaches to inhibit malignant transformation by modulating reciprocal signalling between prostate cancer cells and their tumour-promoting microenvironment.

Appl Opt 58 5 , AA MCP Nov 7, doi: J Neurosci. Hum Mol Genet. Sep 19, published ahead of print. Cheresh, D. Shattil, S. Hogervorst, F. Springer, T. Huang, C. Li, R. Kishimoto, T. Law, S. Green, L. Brown, N. Baum, P. Brower, D. Bogaert, T. Wehrli, M. Stark, K. Song, W. Cell Sei.

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Burkin, D. Hughes, A. Butler, W. Tissue Res.

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Ross, R. Pham, C. Heart Circ. Nagai, T. Brilla, C.

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Heart J. Weber, K. Bashey, R. Cell Cardiol. Kawano, H. Terracio, L. Maitra, N. Burgess, M. Carver, W. Hsueh, W. MacKenna, D. Figure 1 Adhesions mediated via different integrins induce the assembly of morphologically distinct focal adhesions.

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Figure 2 Signalling by nanopatterned substrates. Further Reading.

The extracellular matrix and cell wall

Nano-topography sensing by osteoclasts. Journal of Cell Science. Induction of cell polarization and migration by a gradient of nanoscale variations in adhesive ligand spacing. Nano Letters. Environmental sensing through focal adhesions. Nature Reviews Molecular Cell Biology. Scientific Activities Nano-architecture of adhesion complexes Cell-adhesion sensing of the extracellular matrix Cancer adhesion and invasion Mechanosensitivity of integrin adhesions Cell biology of osteoclasts Adhesion-mediated signaling Platelet adhesion Quantitative automated microscopy for high-throughput screening Adhesion diversity and the integrin adhesome network Adhesion of immune cells Heart muscle development Publications Group Members Collaborations Screening Projects Software Galleries Research. Nano-architecture of adhesion complexes. Cell-adhesion sensing of the extracellular matrix.