When cells adhere to and interact with their surroundings in tissues, they generate and transmit molecular signals that control how the cells behave, such as whether they move, grow or divide. Molecules that carry these signals are often modified temporarily to switch the signals on or off. One important type of biochemical modification is phosphorylation, which plays a role in many cell signalling processes, including cell adhesion.
Adhesion signalling molecules activated by phosphorylation
Joe Robertson, and others in Martin Humphries’ lab and the mass spectrometry core facility at the University of Manchester, set out to better understand the molecules that transmit signals at points of cell adhesion. These points of attachment contain hundreds of different proteins – so-called adhesion complexes – that act together to signal and control cell behaviour. Working out how phosphorylation contributes to this regulation would advance our knowledge of fundamental aspects of the biochemistry of cells.
In this paper, cell adhesion complexes were isolated and analysed by phosphoproteomics, a technique that measures all the proteins that have phosphorylation modifications and so could be involved in transmitting cellular signals.
The image above represents portions of the adhesion signalling molecule FAK (focal adhesion kinase), which is activated by phosphorylation (yellow glow).1 This activation is performed by another adhesion signalling molecule, Src, a member of a family of molecules that phosphorylate many proteins in the cell. Because there are so many molecules involved in cell adhesion, some of which might not have even been discovered yet, using phosphoproteomics lets us get a much more complete picture of the collection of signalling proteins in adhesion complexes.
This large-scale analysis of adhesion complexes revealed a remarkably high abundance of phosphorylation at points of cell adhesion, suggesting a critical and widespread role for phosphorylation in adhesion signalling. Comparison of the levels of phosphorylation showed that some adhesion proteins switch on their signals when cells adhere to their surroundings. Other proteins do not require cell adhesion to become phosphorylated, but travel to points of cell adhesion anyway, already switched on, bringing their phosphorylation signals with them.
Further work is needed to understand precisely what these different types of signalling proteins are doing in adhesion complexes and how this is controlling cell behaviour. But these data lay the foundation for us to understand how signalling might be working during cell adhesion.
Note
1For the image, I rendered the parts of FAK using the crystal structure of the kinase domain of active FAK phosphorylated on tyrosine residues 576 and 577 (PDB code 2J0L) as a template.
Funding
This work was supported by the Wellcome Trust, the BBSRC and the University of Manchester.
Citation
Robertson et al. Defining the phospho-adhesome through the phosphoproteomic analysis of integrin signalling. Nat. Commun. 6, 6265 (2015)
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Adam Byron 