Extension Pause and Stasis

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Steps in Formation

1. Initiation and Nucleation
2. Extension, Pause and Stasis
3. Formation of Adhesions
4. Force Generation and Translocation
5. Disassembly of actin filaments and adhesions

Functional Modules

Lamellipodia and Lamella

Step 2: Extension, Pause and Stasis

The dynamic nature of the actin cytoskeleton requires the continual nucleation of new filaments or new filament branches. Extension of these newly formed branches occurs at the interface between the leading edge and the existing actin filament network [1] and is maintained by mechanisms such as actin treadmilling. Extending filaments push against the membrane, creating a protrusive force that drives both lamellipodial growth, as well as overall cell motility [2].

Extension
Filament extension occurs via the ‘actin treadmilling’ mechanism, with lamellipodial growth reflecting the balance between actin filament polymerization at the barbed ends and retrograde actin flow towards the cell body (reviewed in [3]). Motile cells adjust the rate of actin assembly in specific regions of the cell to outpace retrograde flow, thereby favoring cell contact and protrusion in a particular direction [4]. In certain motile cells (e.g. fish keratocytes), the actin cytoskeleton remains stationary relative to the substratum, indicating that there is virtually no retrograde actin flow and therefore the rate of actin polymerization equals the rate of protrusion [5].

Lamellipodial extension is often coupled to larger events that facilitate cell motility and mechanosensing. For example, extension of the actin filament network is essential in periodic contractions. This process, is primarily driven by myosin motor proteins (see ‘Functional Module: Myosin II in Filament Retraction’) and allows the cell to sense and measure the rigidity of its surroundings. Myosin motors localize behind the actin filament network, making filament extension essential to facilitate the rearward movement of older filaments towards these motors – a process resulting from the retrograde movement that occurs during filament extension.

Along with periodic contractions, lamellipodial extension may also occur along with peripheral membrane ruffling or with circular dorsal ruffles.

Pause and Stasis
Although the lamellipodial actin network is highly dynamic, moments of pause and stasis have been reported [6]. This has been correlated to the angle of actin filaments at the membrane interface, with a greater number of ‘low angle’ filaments being seen to align in parallel to the leading edge during longer pauses [6]. These ‘low angle’ filaments continue to extend whilst shorter ‘high angle’ filaments depolymerize, resulting in a net reduction in protrusion [6]. Pause and stasis also allow time for maturation and elongation of nascent focal adhesions along the actin network [7]. This has been shown to occur particularly at the interface of lamellipodia and lamellae [7].

References

Lai FP., Szczodrak M., Block J., Faix J., Breitsprecher D., Mannherz HG., Stradal TE., Dunn GA., Small JV. & Rottner K. Arp2/3 complex interactions and actin network turnover in lamellipodia. EMBO J. 2008; 27(7):982-92. [PMID: 18309290]
Peskin CS., Odell GM. & Oster GF. Cellular motions and thermal fluctuations: the Brownian ratchet. Biophys. J. 1993; 65(1):316-24. [PMID: 8369439]
Insall RH. & Machesky LM. Actin dynamics at the leading edge: from simple machinery to complex networks. Dev. Cell 2009; 17(3):310-22. [PMID: 19758556]
Forscher P., Lin CH. & Thompson C. Novel form of growth cone motility involving site-directed actin filament assembly. Nature 1992; 357(6378):515-8. [PMID: 1608453]
Theriot JA. & Mitchison TJ. Actin microfilament dynamics in locomoting cells. Nature 1991; 352(6331):126-31. [PMID: 2067574]
Koestler SA., Auinger S., Vinzenz M., Rottner K. & Small JV. Differentially oriented populations of actin filaments generated in lamellipodia collaborate in pushing and pausing at the cell front. Nat. Cell Biol. 2008; 10(3):306-13. [PMID: 18278037]
Choi CK., Vicente-Manzanares M., Zareno J., Whitmore LA., Mogilner A. & Horwitz AR. Actin and alpha-actinin orchestrate the assembly and maturation of nascent adhesions in a myosin II motor-independent manner. Nat. Cell Biol. 2008; 10(9):1039-50. [PMID: 19160484]