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, 73 (6), 1119-30

Molecular Basis of Contact Inhibition of Locomotion


Molecular Basis of Contact Inhibition of Locomotion

Alice Roycroft et al. Cell Mol Life Sci.


Contact inhibition of locomotion (CIL) is a complex process, whereby cells undergoing a collision with another cell cease their migration towards the colliding cell. CIL has been identified in numerous cells during development including embryonic fibroblasts, neural crest cells and haemocytes and is the driving force behind a range of phenomenon including collective cell migration and dispersion. The loss of normal CIL behaviour towards healthy tissue has long been implicated in the invasion of cancer cells. CIL is a multi-step process that is driven by the tight coordination of molecular machinery. In this review, we shall breakdown CIL into distinct steps and highlight the key molecular mechanisms and components that are involved in driving each step of this process.

Keywords: Cadherin; Cell adhesion; Cell migration; Cell polarity; Rac; Rho.


Fig. 1
Fig. 1
The multiply stages of contact inhibition of locomotion. a Free migrating cells show polarised migration: Rac1 activity in the leading edge stimulates protrusion formation. Microtubules stabilise the directional migration of these cells. In addition, focal adhesions generation traction forces enabling the cells to migrate along a substrate. b Initially a contact is formed between the cells: the lamellae of the colliding cells overlap and cell–cell adhesions form between the two cells. The cytoskeletons of the colliding cells become coupled. c Protrusive activity is inhibited at the site of contact: Rac1 activity is lost at the contact site and RhoA become active at the point. This causes the protrusions to collapse and prevents new protrusions from forming at the contact site. d The cells repolarise and new protrusions form away from the contact: Rac1 becomes active in the free edge away from the contact promoting the formation of new protrusions in this area. Focal adhesions form in these new protrusions and stabilises them. Microtubule dynamics increase at the contact site with an increase in growth and shrinkage rates and microtubule catastrophe events. e The cells separate and migrate away from each other: the cells continue migrating in the direction of the newly formed protrusions away from the direction of contact. The cell–cell adhesions disassemble and the cells final separate
Fig. 2
Fig. 2
The RhoGTPase switch at the cell–cell contact. a Cadherin-11 sequesters Trio to the contact where it is inhibited. Trio activates Rac1 and inhibits RhoA. As Trio is sequestered and inhibited at the contact, Rac1 cannot be activated and the inhibition on RhoA is lifted. It is possible that Cadherin-11 inhibits Trio via the recruitment of the polarity protein Par3. b N-cadherin may be influencing the behaviour of the RhoGTPases through several means. One possibility is that it recruits Par3 to the contact and that in turn inhibits Trio. Secondly N-cadherin leads to the inhibition of the GEF—Tiam1 via its association with nm23. Nm23 binds and inhibits Tiam1 at the contact site. Tiam1 is an activator of Rac1 and its inhibition prevent the activation of Rac1 at the contact site. Interaction with p120-catenin is the determining factor influencing the differential behaviour of the RhoGTPases downstream of E- and N-cadherin. It is likely that p120-catenin is signalling through an as yet unidentified means leading to the activation of RhoA and inhibition of Rac1 at the contact. c The non-canonical Wnt-planar cell polarity pathway is activated by Wnt11 binding to the receptor Frizzled. Dishevelled, Prickle1 and Strabismus are recruited to the receptor at the contact upon a collision. The activation of this pathway results in the activation of RhoA near the contact. Due to the shared component p120-catenin it is possible N-cadherin binding stimulates signalling through the planar cell polarity pathway. d EphA binds EphrinA from the neighbouring cell. This stimulates bidirectional signalling that results in the activation of the GEF—Vav2. Vav2 in turn activates RhoA
Fig. 3
Fig. 3
Possible mechanisms stimulating the separation of the colliding cells. a The cell–cell adhesions disassemble or become internalised. This could be triggered by either an addition of tension or a signalling event. The disassembly of the contact between the cells would break the contact and cause the cells to separate. b ROCK activates Myosin II that drives actomyosin contraction near the contact site. This contraction could generate tension across the contact and pull the cells apart. c Microtubules at the contact can restrict the membranes dynamics and give stability to the contact site. If microtubules undergo a sudden catastrophe event this would increase tension across the contact site and this could be sufficient to force the cell–cell adhesions apart causing the cells to separate. d The continuous retrograde flow of actin can generate tension in the lamellae and across both cells when they are coupled through the cell–cell adhesions. This tension could build until it becomes so great it snaps the cell–cell adhesions apart causing the cells to separate. e The repolarisation of the cell away from the contact, driven by Rac1 activity and focal adhesions stabilising the new protrusions, can generate tension across the whole cell. This could be sufficient to drive the separation of the cells

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