Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation

Yang, Jr-Ming; Bhattacharya, Sayak; West‐Foyle, Hoku; Hung, Chien-Fu; Wu, Tung‐Kung; Iglesias, Pablo A.; Huang, Chuan Hsiang

doi:10.1038/s41467-018-07150-9

Cited by 57 publications

(67 citation statements)

References 65 publications

(76 reference statements)

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“…Perturbations equivalent to oncogenic mutations alter the wave properties, causing cells to display wider or longer, narrower protrusions (4,8). Human cancer cell lines also display altered morphology and migratory behavior which can be traced to network excitability (9,10).…”

Section: Pten -/-mentioning

confidence: 99%

Statin-induced GGPP depletion blocks macropinocytosis and starves cells with oncogenic defects

Jiao

Cai

Lan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Cancer cells display novel characteristics which can be exploited for therapeutic advantage. Isolated studies have shown that 1) the mevalonate pathway and 2) increased macropinocytosis are important in tumorigenesis, but a connection between these two observations has not been envisioned. A library screen for compounds that selectively killed Dictyostelium pten− cells identified pitavastatin. Pitavastatin also killed human breast epithelial MCF10A cells lacking PTEN or expressing K-RasG12V, as well as mouse tumor organoids. The selective killing of cells with oncogenic defects was traced to GGPP (geranylgeranyl diphosphate) depletion. Disruption of GGPP synthase in Dictyostelium revealed that GGPP is needed for pseudopod extension and macropinocytosis. Fluid-phase uptake through macropinocytosis is lower in PTEN-deleted cells and, as reported previously, higher in cells expressing activated Ras. Nevertheless, uptake was more sensitive to pitavastatin in cells with either of these oncogenic mutations than in wild-type cells. Loading the residual macropinosomes after pitavastatin with high concentrations of protein mitigated the cell death, indicating that defective macropinocytosis leads to amino acid starvation. Our studies suggest that the dependence of cancer cells on the mevalonate pathway is due to the role of GGPP in macropinocytosis and the reliance of these cells on macropinocytosis for nutrient uptake. Thus, inhibition of the networks mediating these processes is likely to be effective in cancer intervention.

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Section: Pten -/-mentioning

confidence: 99%

Statin-induced GGPP depletion blocks macropinocytosis and starves cells with oncogenic defects

Jiao

Cai

Lan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Studies in Dictyostelium have shown that in the absence of signal transduction, these cytoskeletal events generate short, narrow protrusions, whereas coupling of STEN and CEN produces waves at the edge of cells followed by forward expansion of the membrane in the form of pseudopodia or broad lamellipodia-like protrusions , Miao et al, 2019, Tang et al, 2014, Vicker, 2002. Such correlations between signal transduction and actin waves, and leading edge protrusions are also found in mammalian cells such as neutrophils (Weiner et al, 2007), fibroblasts (Jalal et al, 2019, Zhang et al, 2018, keratocytes (Barnhart et al, 2011) and cancer cells (Yang et al, 2018).…”

Section: Role Of Excitability In Dictyostelium and Mammalian Cellsmentioning

confidence: 92%

The excitable signal transduction networks: movers and shapers of eukaryotic cell migration

Pal¹,

Li²,

Banerjee³

et al. 2019

Int. J. Dev. Biol.

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In response to a variety of external cues, eukaryotic cells display varied migratory modes to perform their physiological functions during development and in the adult. Aberrations in cell migration result in embryonic defects and cancer metastasis. The molecular components involved in cell migration are remarkably conserved between the social amoeba Dictyostelium and mammalian cells. This makes the amoeba an excellent model system for studies of eukaryotic cell migration. These migration-associated components can be grouped into three networks: input, signal transduction and cytoskeletal. In migrating cells, signal transduction events such as Ras or PI3K activity occur at the protrusion tips, referred to as 'front' , whereas events such as dissociation of PTEN from these regions are referred to as 'back' . Asymmetric distribution of such front and back events is crucial for establishing polarity and guiding cell migration. The triggering of these signaling events displays properties of biochemical excitability including all-or-nothing responsiveness to suprathreshold stimuli, refractoriness, and wave propagation. These signal transduction waves originate from a point and propagate towards the edge of the cell, thereby driving cytoskeletal activity and cellular protrusions. Any change in the threshold for network activation alters the range of the propagating waves and the size of cellular protrusions which gives rise to various migratory modes in cells. Thus, this review highlights excitable signal transduction networks as key players for coordinating cytoskeletal activities to drive cell migration in all eukaryotes.

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“…2F), suggesting a loss of coordinated retraction and repolarisation of lamellae after collision. Interestingly, ERK proteins were recently shown to regulate various cytoskeletal and migratory behaviours (Yang et al, 2018; Mendoza et al, 2011; Aoki et al, 2017) and we hypothesise that the ERK family is a good candidate to modulate distinct CIL dynamics.…”

Section: Resultsmentioning

confidence: 93%

Heterotypic contact inhibition of locomotion can drive cell sorting between epithelial and mesenchymal cell populations

Brayford

Kenny

Hiratsuka

et al. 2019

Journal of Cell Science

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Interactions between different cell types can induce distinct contact inhibition of locomotion (CIL) responses that are hypothesised to control population-wide behaviours during embryogenesis. However, our understanding of the signals that lead to cell-type specific repulsion and the precise capacity of heterotypic CIL responses to drive emergent behaviours is lacking. Using a new model of heterotypic CIL, we show that fibrosarcoma cells, but not fibroblasts, are actively repelled by epithelial cells in culture. We show that knocking down EphB2 or ERK in fibrosarcoma cells specifically leads to disruption of the repulsion phase of CIL in response to interactions with epithelial cells. We also examine the population-wide effects when these various cell combinations are allowed to interact in culture. Unlike fibroblasts, fibrosarcoma cells completely segregate from epithelial cells and inhibiting their distinct CIL response by knocking down EphB2 or ERK family proteins also disrupts this emergent sorting behaviour. These data suggest that heterotypic CIL responses, in conjunction with processes such as differential adhesion, may aid the sorting of cell populations.

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Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation

Cited by 57 publications

References 65 publications

Statin-induced GGPP depletion blocks macropinocytosis and starves cells with oncogenic defects

Statin-induced GGPP depletion blocks macropinocytosis and starves cells with oncogenic defects

The excitable signal transduction networks: movers and shapers of eukaryotic cell migration

Heterotypic contact inhibition of locomotion can drive cell sorting between epithelial and mesenchymal cell populations

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