Martin Humphries
LAB

Our discoveries



Helping cells to get a grip!

Written by Paul Mould


The meshwork of proteins that surrounds cells is called the extracellular matrix. Cells need to grip onto the matrix in order to grow, survive and move. However, cells have to carefully control their “stickiness”: too much and the cells are stuck fast and can't move; too little and the cells shrivel up and die. Proteins found on the surface of cells, known as integrins, are very important in helping cells to control their stickiness.


How do integrins do this? For a number of years it has been thought that integrin molecules can rapidly change their shape from a bent form to an extended form. This shape change looks rather like a man who is crouching down then suddenly standing up tall. However, it was uncertain whether this change of shape was important for making cells stick to the matrix.

In this publication, we have used a powerful light microscope to study parts of the cell surface, known as focal adhesions, where the cell is attached to the matrix. We show that within these focal adhesions integrins have a “tall” shape. On the other hand, integrin molecules that stay in a “crouching” shape are unable to help cells attach. In summary, this piece of research shows that shape changes in integrin molecules play an essential role in helping cells to get just the right amount of grip.

  

Citation

JA Askari, CJ Tynan, SE Webb, ML Martin-Fernandez, C Ballestrem and MJ Humphries (2010) Focal adhesions are sites of integrin extension. J. Cell Biol. 188: 891-903. Full text | PubMed entry


Further information

Cell Migration Gateway Featured Article: Integrin structure: Importance of extension

Faculty of 1000 Biology evaluation




“Shooting in the dark” may help to prevent blindness

Written by Paul Mould


Abnormal growth of blood vessels in the eye results in age-related macular degeneration (AMD), the leading cause of blindness among individuals aged 50 years and older in developed countries. Integrins are a family of proteins found on the surface of cells that have important roles in promoting blood vessel formation. Drugs that can block the function of integrins have been shown to prevent blood vessel growth, and these drugs are currently being trialled as a potential new treatment for AMD. However, we only have a limited understanding of how these drugs work.


Finding really effective drugs depends on having a good appreciation of how these molecules interact with integrins. It's rather like needing to know the exact shape of the “lock” (the integrin) before we can design really effective “keys” (the drugs).

In this paper, we use a clever technique (called a “gain-of-function” approach) to identify the precise regions of the integrin α5β1 that form a binding site for molecules that can block its function. This technique involves a bit of “shooting in the dark”: randomly replacing parts of the integrin from one species (human) with the equivalent parts from a different species (zebrafish).


The outcome of this research is that we now have an improved understanding of how to design new drugs that are a better fit for the integrin. The hope is that these new drugs will prove to be more powerful and efficacious in treating eye disease.

Citation

AP Mould, EJ Koper, A Byron, G Zahn and MJ Humphries (2009) Mapping the ligand-binding pocket of integrin α5β1 using a gain-of-function approach. Biochem. J. 424: 179-89. Full text | PubMed entry




Cell breakthrough opens a new chapter in drug development

Written by Aeron Haworth, Adam Byron, Jon Humphries and Martin Humphries


Cells in our bodies communicate with each other and their environment through a complex process called “signalling”. Cell signalling is essential for life, and when it goes wrong, it can lead to many different kinds of disease, including arthritis, diabetes and cancer.

Signalling allows cells to sense the thousands of molecules that make up their immediate environment. How cells send and receive signals using “receptors” on their outer skins (or “membranes”) has been known for some time, but much of what happens afterwards inside the cell has not been fully understood. As a result, many drugs on the market work without scientists knowing precisely how they affect cell function.


We have now developed a technique that will allow scientists to examine how the receptors on the surface of cells pass information to the hundreds of proteins inside the cell that create the signal. Uniquely, our findings will allow scientists to look at all these hundreds of components at the same time.

  

Our findings will finally allow scientists to observe how drugs work at an intracellular level, which will allow them to fully understand how they interact with the hundreds of cell receptors at the same time and what side-effects they are likely to produce. This research will hopefully lead to better drug design and faster drug delivery times. In addition, the findings will also provide biologists with a completely new insight into how our bodies work.


Our findings will be of great interest to scientists and pharmaceutical companies as they open up new avenues for drug development and testing.

Citation

JD Humphries*, A Byron*, MD Bass, SE Craig, JW Pinney, D Knight and MJ Humphries (2009) Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Sci. Signal. 2: ra51. Full text | PubMed entry


Further information

Press release: University of Manchester | EurekAlert | AlphaGalileo | ScienceDaily

Science Signaling Editor's Summary: Integrin interactors

Science Signaling Perspective: Integrin proteomes reveal a new guide for cell motility

Science Signaling Editorial Guide: 2009: Signaling breakthroughs of the year

University of Manchester Faculty of Life Sciences highlight research publication

Faculty of 1000 Biology evaluation




*These authors contributed equally to this work.