Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Cellular directionality To obtain a comprehensive underst

    2021-10-14


    Cellular directionality To obtain a comprehensive understanding of cell migration, it is essential to understand how cues from the cell’s external environment are relayed to the histamine inhibitors cytoskeleton, so the cell can migrate towards the cue; a process herein referred to as cellular directionality. Understanding cellular directionality is particularly important for the cell migration field as motile cells must be able to both prioritise external cues and rapidly change direction in response to an ever-changing external environment. Whilst the types of cue that can trigger cell migration (e.g. chemokines, matrix-derived etc.) have been well described, the search for an internal ‘compass’ has proven somewhat difficult [24,25]. Whilst for years this role was thought to be provided by PI3 kinase, the discovery that cells can migrate in the absence of this kinase re-opened this question [26, 27, 28]. Increasingly however, the Rho-family GTPases have been implicated in this role. For example Rac1 signalling can relay directional information between Drosophila border cells migrating as a cluster in vivo, via E-cadherin mediated mechano-sensing [29]. Similarly, P-cadherin mediated mechano-transduction can drive cell polarisation during collective mouse myoblast migration in a 2D culture system, by signalling to Cdc42 [30] (Figure 2a). Cdc42 has also been implicated as an internal compass during neutrophil migration. In order to successfully trap and destroy motile bacteria, neutrophils must rapidly respond to the ever changing position of the bacterium [31]. Rho-GTPase FRET sensors, in combination with photoactivatable chemokines demonstrated a role for Cdc42 in responding to the chemokine and controlling neutrophil steering (and suppression of RhoA), whereas a shallow gradient of Rac activity more distal to the leading edge might provide the ‘engine’ []. This neutrophil study was performed in 2D culture, and thus it remains to resolved if Cdc42 performs this role during in vivo migration, whereby the neutrophil must integrate and prioritise numerous migratory cues. It is interesting to note that Rac1 and Cdc42 have both been shown to control cellular directionality: Rac1 in the collective migration of Drosophila border cells [29] and in fibroblasts [33] and Cdc42 in both collective cell migration and in neutrophils [,30]. Cdc42 would seem to be the more obvious candidate as a universal compass, should such an entity exist, given its defined role in establishing cell polarity [34,35]. However, given the significant differences between the cell types used in these studies, and the difficulty of finding a universal compass that controls the directionality of a migrating cell, it is likely that different members of the Rho family of GTPases can serve as a compass in a context-dependent manner.
    Signalling to Rho-family GTPases Since the discovery of small GTPases, many questions have persisted as to the nature of the GEFs and GAPs that control the on/off cycle of these switches [1]. Rho-family GTPases are no exception, and despite numerous regulators having been identified, it is still not clear why there are so many or how much functional redundancy exists. Answering these questions is essential as GEFs and GAPs provide an interface through which the cell is able to communicate to Rho-family GTPases [1]. Recently, work from Marei et al. has addressed this question in a mammalian culture system, confirming the relevance of previous studies in yeast. In the NIH3T3 mouse embryonic fibroblast cell line, the Rac GEF P-Rex1 promoted cell migration in 2D and a more contractile phenotype in 3D, whilst TIAM1 signalled to block migration. The key to these differential outcomes seemed to be dependent on P-Rex1 enhancing the interaction of Rac1 with FLI2 [36,37,]. This work suggests that GEFs may serve to function as more than just ‘switch flippers’ and act to direct Rho GTPase signalling via specific effector pathways (Figure 1).