The movement of cells in the body is of great importance to our lives. For us to learn a language, to fight a cold, to heal a wound, to grow a pair (of arms, say), cells must migrate to the right place at the right time. So cell migration must be tightly controlled – throughout our entire lives.
Cells have many in-built control mechanisms that ensure their appropriate movement, but we still don’t fully understand how these various mechanisms operate.
In new work, published in the Journal of Cell Science this week, Guillaume Jacquemet and others identify a way that cells can coordinate proper cell migration. The research is highlighted by the journal editors and features on the cover of the journal.
Journal of Cell Science cover, 2013, vol. 126 (no. 18)
Just like walking in a straight line, putting one foot in front of the other, cells extend and retract areas of their outer membrane to move through our bodies. (The image on the journal cover, above, illustrates how the edge of a cell moves over time.) These events are coordinated by reorganisation of cytoskeleton, the “bones” of the cell, which enables cells to move in a specific direction.
Cells determine which way to travel (and when) by using receptors on their surface that can sense various aspects of the microenvironment, such as its chemical composition or its rigidity. These receptors pass on the message from the microenvironment to molecules inside the cell in a process called signal transduction.
For signal transduction to work, signalling molecules in the cell must be switched on at the right place when there is a message to pass on, but also must be switched off when they have done their job. This allows them to be used again and again by the cell and allows cell signalling to be rapid.
This cycling of localised signalling activity is an important principle in cell migration – and much of cell biology.
The research in this paper identifies the molecules filamin-A and IQGAP1 as regulators of the activity of Rac1, a small GTPase that switches on and off to control cell migration. The work goes on to show that IQGAP1 can recruit RacGAP1 – a molecule that switches off Rac1.
At sites of active integrin (cell surface receptors that sense the microenvironment), a complex of filamin-A, IQGAP1 and RacGAP1 is formed. This protein complex switches off Rac1, which prevents unconstrained membrane protrusion and dysregulated cell migration.
Turning a signal off is just as important as turning it on!
A related paper published in the Journal of Cell Biology (also this week) examines how localised GTPase signalling is sustained in cancer cells. Where Rac1 is switched off in cells, the related small GTPase RhoA can be switched on. This shift in related GTPases promotes cytoskeleton-dependent membrane protrusions called pseudopodia (“false feet“), which many cancer cells use to metastasise and invade tissue.
Interestingly, this coordination of cell signalling and migration is dependent on the composition of the extracellular microenvironment. Cell migration on extracellular matrix rich in fibronectin triggers a cascade of molecular events in the cell, driven by the trafficking of integrin receptors, which promotes invasion into the microenvironment.
Tight control of cell migration is essential for normal cellular function but also determines how tumour cells metastasise in cancers. These new findings improve our understanding of how cells migrate and provide clues as to how we may be able to intervene in processes of disease pathogenesis, such as tumour cell invasion.
In cell signalling, turning a signal off is just as important as turning it on!
Funding: This work was supported by the Wellcome Trust.
Citation: G Jacquemet, MR Morgan, A Byron, JD Humphries, CK Choi, CS Chen, PT Caswell, MJ Humphries, Rac1 is deactivated at integrin activation sites through an IQGAP1–filamin-A–RacGAP1 pathway. J. Cell Sci. 126, 4121–4135 (2013). HTML | PDF | PubMed
Adam Byron 
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