Characterisation of a nucleo-adhesome

A study by scientists at the Institute of Genetics and Cancer provides important new information about the ability of cell adhesion molecules to relocate to the cell nucleus.

When you look at a eukaryotic cell under a microscope, the nucleus is one of the most obvious parts. It contains the cell's genetic material (also known as the genome) and is a site of genetic transcription that allows for precise regulation of gene expression - the process by which instructions in DNA are converted into a functional product, such as a protein. Sophisticated regulation of gene expression allows a single cell with a single genome to give rise to a large number of progeny cells with very different characteristics. An excellent example of this is human embryogenesis, where a single fertilised egg can give rise to millions of cells as diverse as neurons, skin cells, and muscle cells. Abnormalities in gene expression are often associated with serious diseases, including cancer.

Cell adhesion is the process by which cells interact and attach to neighbouring cells or their nearby environment (the so-called extracellular matrix). This is mediated by special molecules on the cell surface. These adhesion molecules (collectively called adhesome) cluster at the points of cell adhesion and form sophisticated multimolecular complexes that are essential for the physiological functions of cells in tissues. Adhesion molecules are connected to multiple signal communication pathways within cells, making these cell-cell and cell-matrix interactions critical for many biological processes such as cell survival, differentiation, and migration. For a long time, it was assumed that there was not much interaction between proteins regulating nuclear functions and cell adhesion proteins. However, recent findings strongly suggest that some cell adhesion proteins can migrate into the nucleus and play an important role in controlling gene expression there. For example, researchers from Edinburgh demonstrated that Focal Adhesion Kinase (FAK), a protein involved in regulation of the cytoskeleton and assembly of some adhesion sites, can control the expression of important genes and, through this process, help cancer cells evade anti-tumour immunity. Nevertheless, the true extent of nuclear localization and the nuclear functions of adhesion proteins are still largely unknown.

We found that an unexpectedly large number of adhesion proteins are also found in the nucleus. We made this discovery by cataloguing the molecular make-up of nuclei from skin cancer cells. This gives us a new level of understanding of the remarkable extent to which this family of molecules relocates to the genetic control centre of the cell. What these molecules are collectively doing in the nucleus remains to be discovered, but we show in this study for the first time that multiple adhesion proteins can work together in the nucleus to switch on genes in cancer cells. This new understanding of cell biology opens the door to finding new ways that cells control their genes, and this is a valuable starting point for figuring out if – and how – these features go awry in cancer.

In a recent study published in Nature Communications titled "Characterisation of a nucleo-adhesome," the Edinburgh team combined state-of-the-art cell fractionation methods with high-end protein analysis technologies (proteomics) and protein network studies to characterise a nucleo-adhesome - a set of proteins that can be found both at the cell adhesion sites as well as in the nucleus - in squamous cell carcinoma cells (a form of skin cancer). Surprisingly, more than half of the proteins found in the so-called consensus adhesome (a core set of 60 frequently identified adhesion proteins) were shown to localise to the nucleus. The data provide a solid foundation for developing a better understanding of the extent and functions of nucleo-adhesome proteins.

The authors also demonstrated that nuclear FAK transcriptionally regulates the expression of a subset of adhesion proteins that can be localised to the nucleus, and demonstrated that nuclear adhesion proteins can co-associate and co-regulate a subset of genes via transcription, further emphasising the role cell adhesion proteins can play in the regulation of gene expression. The work was led by Dr. Adam Byron and Prof. Margaret Frame of the Institute of Genetics and Cancer at the University of Edinburgh. It was funded by Cancer Research UK and supported by the Wellcome Trust.

Characterisation of a nucleo-adhesome

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