An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo

Lin, Benjamin; Luo, Jonathan; Lehmann, Ruth

doi:10.1126/sciadv.abo0323

Cited by 11 publications

(21 citation statements)

References 76 publications

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“…While there is scarce evidence for other kinases regulating MLC2 function via MYPT in migrating cells, we suggest that AMPK phosphorylation of Ser472-MYPT1 may be a key controller of tumour cell migratory plasticity downstream of mechano-metabolic signals. However, AMPK may regulate Myosin II activity at multiple levels, as AMPK activates RhoA signalling via phosphorylation of RhoGEF2 in migrating Drosophila primordial germ cells 49 .…”

Section: Discussionmentioning

confidence: 99%

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration

et al. 2023

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Cell migration is crucial for cancer dissemination. We find that AMP-activated protein kinase (AMPK) controls cell migration by acting as an adhesion sensing molecular hub. In 3-dimensional matrices, fast-migrating amoeboid cancer cells exert low adhesion/low traction linked to low ATP/AMP, leading to AMPK activation. In turn, AMPK plays a dual role controlling mitochondrial dynamics and cytoskeletal remodelling. High AMPK activity in low adhering migratory cells, induces mitochondrial fission, resulting in lower oxidative phosphorylation and lower mitochondrial ATP. Concurrently, AMPK inactivates Myosin Phosphatase, increasing Myosin II-dependent amoeboid migration. Reducing adhesion or mitochondrial fusion or activating AMPK induces efficient rounded-amoeboid migration. AMPK inhibition suppresses metastatic potential of amoeboid cancer cells in vivo, while a mitochondrial/AMPK-driven switch is observed in regions of human tumours where amoeboid cells are disseminating. We unveil how mitochondrial dynamics control cell migration and suggest that AMPK is a mechano-metabolic sensor linking energetics and the cytoskeleton.

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Section: Discussionmentioning

confidence: 99%

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration

et al. 2023

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“…Oscillation of RhoA activity has been attributed to a combination of positive and negative feedbacks. RhoA signaling can be amplified by local accumulation of active RhoA through advection (Munjal et al, 2015) or slowed diffusion (Graessl et al, 2017), RhoGEF recruitment by active RhoA (Graessl et al, 2017; Lin et al, 2021) or microtubules (Azoitei et al, 2019; Lin et al, 2021), and stress-induced RhoA activation (Bailles et al, 2019). On the other hand, active RhoA can be turned off by the accumulation of actomyosin (Munjal et al, 2015) and delayed RhoGAP recruitment — often through F-actin — (Graessl et al, 2017; Michaux et al, 2018; Segal et al, 2018), and myosin II-independent ROCK signaling (Ong et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Pulses of RhoA Signaling Stimulate Actin Polymerization and Flow in Protrusions to Drive Collective Cell Migration

Qian,

Yamaguchi,

Lis

et al. 2023

Preprint

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SummaryIn animals, cells often move as collectives to shape organs, close wounds, or—in the case of disease—metastasize. To accomplish this, cells need to generate force to propel themselves forward. The motility of singly migrating cells is driven largely by an interplay between Rho GTPase signaling and the actin network (Yamada and Sixt, 2019). Whether cells migrating as collectives use the same machinery for motility is unclear. Using the zebrafish posterior lateral line primordium as a model for collective cell migration, we find that active RhoA and myosin II cluster on the basal sides of the primordium cells and are required for primordium motility. Positive and negative feedbacks cause RhoA and myosin II activities to pulse. These pulses of RhoA signaling stimulate actin polymerization at the tip of the protrusions and myosin II-dependent actin flow and protrusion retraction at the base of the protrusions, and deform the basement membrane underneath the migrating primordium. This suggests that RhoA-induced actin flow on the basal sides of the cells constitutes the motor that pulls the primordium forward, a scenario that likely underlies collective migration in other—but not all (Bastock and Strutt, 2007; Lebreton and Casanova, 2013; Matthews et al., 2008)—contexts.

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“…For live imaging of suntag-nanos mRNA translation, we expressed UAS-suntag-nos (WT or SREmut) with a weak Matα-GAL4 (without VP16) maternal driver line to prevent scFv-GFP depletion which can cause artifact (Extended Data Fig. 2) 14,15 . Unfertilized embryos were collected from Vasa-mApple/Matα-GAL4; uas-suntag-nos (WT or SREmut)/scFv-GFP virgin female flies that mated with sterile male flies (male progeny of osk301/oskCE4 flies).…”

Section: Methodsmentioning

confidence: 99%

Repressor sequestration activates translation of germ granule localized mRNA

Chen,

Stainier,

Dufourt

et al. 2023

Preprint

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Biomolecular condensates organize and compartmentalize biochemical processes within cells. Among these, ribonucleoprotein (RNP) granules are characterized as storage depots for translationally repressed mRNA. Whether RNP granules can also activate translation and how such translation is achieved remains unclear. This question is particularly relevant for embryonic germ granules, whose activity has been linked to germ cell fate. Here, we use single-molecule imaging to show that embryonic germ cell RNP granules in Drosophila are the sites of active translation for nanos mRNA. Translating nanos mRNA is oriented with the 5'end preferentially at the germ granule surface while the 3'UTR is buried within the granule. Untranslated nanos mRNAs remain internal within the granule. Quantitative analysis of translational kinetics demonstrates that germ granules activate translation by antagonizing translational repression rather than changing the rate or efficiency of translation. We generated separation-of-function mutations in the disordered linker region of the scaffold protein Oskar that specifically impede nanos translation without affecting germ granule morphology or RNA localization. These mutations reveal that nanos translation is dependent on the sequestration of translational repressors within germ granules. Together, our findings show that RNP granules regulate localized protein synthesis through compartmentalized relief of translational repression raising the possibility that similar repressor-activator switches control translation in other condensates.

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An AMPK phosphoregulated RhoGEF feedback loop tunes cortical flow–driven amoeboid migration in vivo

Cited by 11 publications

References 76 publications

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration

AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration

Pulses of RhoA Signaling Stimulate Actin Polymerization and Flow in Protrusions to Drive Collective Cell Migration

Repressor sequestration activates translation of germ granule localized mRNA

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