Mechanism of cell rear retraction in migrating cells

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Highlights

  • Alternative actin-based forces drive cell rear retraction in migrating cells.

  • These are actin depolymerisation-based, actin crosslinking-based and cell protrusion-based.

  • These are likely important when weaker forces are sufficient for cell rear retraction.

  • Myosin II-motor-based force drives rear retraction during more stringent environments.

  • Myosin II-motor-based force and alternative actin-based forces for rear retraction exist within the same cell.

For decades, ever growing data on myosin II provides strong evidence that interaction of myosin-II-motor-domain with actin filaments within cells retracts the cell rear during actin-based cell migration. Now it is clear myosin II motor-activity is not the sole force involved. Alternative force-generating mechanisms within cells clearly also exist to power cell rear retraction during actin-based cell migration. Given that nematode sperm cells migrate without actin and without cytoskeletal motor proteins it is perhaps not surprising other types of force power cell rear retraction in actin-based systems. Here, cell rear retraction driven by actin filament depolymerisation, actin filament crosslinking, cell front protrusion and possibly apparent membrane tension and their importance relative to myosin II-motor-based contractility are discussed.

Section snippets

More than one type of motile force drives cell rear retraction

For myosin II-motor-based cell rear retraction in motile cells [1, 2, 3, 4] there are differences in the way in which motor-based contractile force is generated (Figure 1a–c), but for all migrating cells so far tested classic contraction-force similar to muscle sarcomeres is the least abundant [5, 6] (Figure 1a). This is due to key differences in actin filament organisation discovered in migrating cells which have the wrong actin filament polarity to allow sarcomeric-type contraction force

Force from cell protrusion drags the cell rear forwards

One earlier idea [1] to explain why in some cells, myosin II-motor-based contractility could only account for some of the motile force needed to retract the cell rear was that force from cell protrusion contributes to pulling the cell rear forwards. In other words the cell rear is a passive passenger pulled along by a protruding cell front. A recent careful study has provided direct evidence for such a model in migrating whole keratocytes [23••]. Inhibition of myosin II-contractility either

Actin filament depolymerisation-based and actin filament crosslinking-based contraction directly pulls the cell rear forwards

In nematode worm sperm cells, which lack actin and cytoskeletal motor proteins, retraction of the cell rear and cell body is instead driven by contractile force derived from either depolymerisation of MSP polymers [26, 27, 28••] or MSP depolymerisation coupled with subsequent crosslinking of shortened MSP polymers [29••]. Previously it has been argued whether force could be derived from similar actin behaviour; compare [29••] and [27]. Now for the first time both actin filament cross-linking [

Inwards, apparent membrane tension retracts the cell rear?

For the cell front, there is direct experimental data in migrating cells and a mathematical model that apparent plasma membrane tension, an inwards force, causes retraction of the cell front and can regulate cell front protrusion [34, 35••, 36••]. What of the cell rear? Mathematical modelling of keratocyte motility, although not the main part of the model, similarly proposes that an increase in membrane tension relative to a weakened underlying actin cytoskeleton pushes on the cell rear to

Comparison of mechanisms

The supply of force that is linked to driving cell rear retraction is distinct in each mechanism proposed (Figure 2) — either actin filament assembly indirectly pulls (Figure 2a), actin filament crosslinking pulls (Figure 2b), actin filament depolymerisation pulls (Figure 2c) or membrane tension pushes (Figure 2d) the cell rear forwards. Actin polymerisation as a supply of force (Figure 2a) is also separately localised within the cell front to all the others (Figure 2b–d) that operate directly

Relative importance of each type of force

It is likely that myosin II motor-based force works together either spatially, temporally, or depending on the context in which the cell moves, with these alternative types of actin-based forces within the same cell to power cell rear retraction (Table 2).

Myosin II-motor-based contractility appears to be the dominant force for cell rear retraction when larger forces are required (Table 1), such as overcoming higher adhesion to the substratum as the cell crawls over increasingly sticky [14] or

Future

The evidence is pointing towards roles for myosin II-motor-based contractility to retract the cell rear when stronger force is needed — such as to pull forwards discrete cell rear zones that are more strongly adherent to the substratum or to pull the entire cell rear over highly sticky or through tightly meshed extracellular environments. On the other hand the notion is that relatively weaker forces coupled to actin filament depolymerisation, actin filament cross-linking and cell protrusion

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (47)

  • L.P. Cramer

    Forming the cell rear first: breaking cell symmetry to trigger directed cell migration

    Nat Cell Biol

    (2010)
  • A.J. Ridley et al.

    Cell migration: integrating signals from front to back

    Science

    (2003)
  • M. Vicente-Manzanares et al.

    Non-muscle myosin II takes centre stage in cell adhesion and migration

    Nat Rev Mol Cell Biol

    (2009)
  • A.B. Verkhovsky et al.

    Network contraction model for cell translocation and retrograde flow

    Biochem Soc Symp

    (1999)
  • L.P. Cramer

    Organization and polarity of actin filament networks in cells: implications for the mechanism of myosin-based cell motility

    Biochem Soc Symp

    (1999)
  • T.M. Svitkina et al.

    Analysis of the actin-myosin II system in fish epidermal keratocytes: mechanism of cell body translocation

    J Cell Biol

    (1997)
  • L.P. Cramer et al.

    Identification of novel graded polarity actin filament bundles in locomoting heart fibroblasts: implications for the generation of motile force

    J Cell Biol

    (1997)
  • N.T. Swailes et al.

    Actin filament organization in aligned prefusion myoblasts

    J Anat

    (2004)
  • T. Mseka et al.

    Graded actin filament polarity is the organization of oriented actomyosin II filament bundles required for fibroblast polarization

    Cell Motil Cytoskeleton

    (2009)
  • D. Knecht et al.

    Antisense RNA inactivation of myosin heavy chain gene expression in Dictyostelium discoideum

    Science

    (1987)
  • A. De Lozanne et al.

    Disruption of the Dictyostelium myosin heavy chain by homologous recombination

    Science

    (1987)
  • P.Y. Jay et al.

    A mechanical function of myosin-II in cell motility

    J Cell Sci

    (1995)
  • K.S.K. Uchida et al.

    Myosin II contributes to posterior contraction and anterior extension during the retraction phase in migrating Dictyostelium cells

    J Cell Sci

    (2003)
  • Cited by (0)

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