When cells move, they alter their internal skeleton to push membrane out at the front and pull it in at the back. New work fills in some of the gaps in our knowledge of how this process is regulated.
Cells come in many different shapes, depending on their function. Neurons, for example, extend long, branching protrusions (axons) to form the web of cellular connections found in the brain. Many other types of cell use changes in their shape to move, and this is an essential property of immune cells, as they crawl through tissues in their search for pathogens. Günther Gerisch's spectacular time-lapse film1 of one such immune cell, a neutrophil, chasing a bacterium highlights the ability of cells to sense external signals and to direct their migration towards them. Not surprisingly, however, cell migration also has its dark side and, when not tightly controlled, can lead to cancer cells invading nearby tissues and spreading through the body. It has long been known that a small protein called Rac acts as a molecular switch that affects many aspects of cell shape and migration2. On page 790 of this issue, Eden and co-workers3 shed light on a new mechanism by which Rac acts upon another key protein in the movement business — WAVE1.
The shape and movement of our cells are controlled by their internal framework, the cytoskeleton. In particular, the highly dynamic and reversible polymerization of a cytoskeletal protein called actin plays a central role in regulating cell behaviour. Actin is soluble when in its monomeric, globular form, but upon polymerization forms insoluble filaments with significant mechanical strength. Localized actin polymerization at the front of a cell pushes its membrane forward in a sheet-like structure known as a lamellipodium2. This can lead to the formation of cell extensions and, when coordinated with contraction at the rear, can propel cells at speeds of up to 30 micrometres a minute.
The rate-limiting step of actin polymerization is the assembly of three actin monomers into a trimer4. So polymerization is enhanced by several factors that stimulate such 'nucleation'. A family of regulatory proteins, including the Wiskott–Aldrich syndrome protein (WASP) and WAVEs 1, 2 and 3, achieve this by interacting with a complex of seven other proteins — the Arp2/3 complex4. When bound by a conserved region within WASP or WAVE (the so-called VCA domain), the Arp2/3 complex is activated and catalyses actin polymerization (Fig. 1), presumably by mimicking an actin trimer. WAVE1 is located at the edges of growing lamellipodia5,6, and drives localized activation of the Arp2/3 complex and actin polymerization at the front of the protrusion.
WASPs and WAVEs are themselves regulated by two other proteins2, Cdc42 and Rac. These are part of a superfamily of proteins that act as specific molecular switches, controlling a plethora of cellular pathways from membrane trafficking to cell growth and division. They are activated by exchanging the small molecule GDP for GTP, and can then interact with certain downstream proteins. So, when active Cdc42 binds to WASP, it disrupts WASP's self-inhibiting structure and exposes the VCA domain, which can thereby activate the Arp2/3 complex (Fig. 1a)4.
In contrast, the WAVE proteins do not contain binding sites for Rac or Cdc42, and so how their activity is controlled has been a mystery. Two years ago it was shown that active Rac binds an intermediary protein (IRSp53), which in turn binds to WAVE2 to activate it7. But this intermediary does not bind WAVEs 1 and 3. Furthermore, it appears that purified WAVE1 is constitutively active3, suggesting that it must somehow be repressed in areas of the cell that are not actively protruding.
Eden and colleagues3 now describe a novel control mechanism whereby WAVE1 is kept inactive, through its association with four other proteins: Nap125, PIR121, Abi2 and the tiny HSPC300. The authors show that this complex is unable to stimulate actin polymerization in an in vitro assay but that the addition of purified, active Rac relieves the inhibition. It does this by binding to the Nap125–PIR121–Abi2 subcomplex and dissociating it from HSPC3000–WAVE1, which can then go on to nucleate actin polymerization (Fig. 1b).
Cdc42 and Rac are not the only keys able to unlock the activity of the WASP and WAVE proteins4. For example, WASP can be activated by binding to SH3 domains8 — modular protein domains found in several signalling molecules — independently of Cdc42. Similarly, Eden et al. show that Nck, a small adaptor protein, can also bind to Nap125–PIR121–Abi2 and induce the dissociation of HSPC3000–WAVE1, independently of Rac. This adaptor also binds to certain receptors on the cell surface, and so may direct the spatial control of WAVE activation and actin polymerization to sites of receptor engagement. Support for this idea comes from studies of enteropathogenic Escherichia coli bacteria, which bind to the outside of cells and recruit cellular Nck (presumably by mimicking a cellular receptor); this in turn causes localized actin polymerization9. Nck also binds to another of Rac's targets, the protein kinase PAK10, and it will be important to work out the relative contributions of Rac and Nck in regulating WAVEs, PAKs and probably other proteins.
Interestingly, Nap125 belongs to a family of transmembrane proteins (the HEM family) that is found in organisms ranging from worms to humans, and it has been implicated in embryo development (itself a process requiring extensive cell movements)11, axon growth12 and the prevention of cell suicide13. Proteins from this family are found in a variety of tissues, including brain and immune cells. Given the results of Eden et al.3, it is possible that these proteins represent an evolutionarily conserved mechanism for regulating cell shape via WAVEs. Abi2 may be important for localizing WAVEs, as it is found at the front of lamellipodia14.
It remains to be seen whether the subcomplex of Nap125, PIR121 and Abi2, bound to Rac or Nck, has a signalling role in its own right, and how interfering with the function of this subcomplex affects cell shape and movement in vitro and in vivo. No doubt there are still more ways to regulate WAVEs, and another question is whether this subcomplex can bind to WAVEs 2 and 3, or whether each WAVE is regulated in a unique way. In any case, these new results3 reveal the complexity of the signalling network surrounding WASP and WAVE proteins, reflecting their role in controlling the multitude of cellular functions governed by the actin cytoskeleton.
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