The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1

Lander, Rachel M.; Nordin, Kara; LaBonne, Carole

doi:10.1083/jcb.201012085

Cited by 123 publications

(124 citation statements)

References 70 publications

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“…EMT depends on transcription factors including Twist and Snail, whose activity is quantitatively regulated at the level of protein stability 46,47 . Little is known about how the transiently expressed Twist protein regulates EMT during embryonic development.…”

Section: Discussionmentioning

confidence: 99%

Interlocked loops trigger lineage specification and stable fates in the Drosophila nervous system

et al. 2014

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Multipotent precursors are plastic cells that generate different, stable fates at the correct number, place and time, to allow tissue and organ formation. While fate determinants are known to trigger specific transcriptional programs, the molecular pathway driving the progression from multipotent precursors towards stable and specific identities remains poorly understood. Here we demonstrate that, in Drosophila neural precursors, the glial determinant glial cell missing (Gcm) acts as a 'time bomb' and triggers its own degradation once the glial programme is stably activated. This requires a sequence of transcriptional and posttranscriptional loops, whereby a Gcm target first affects the expression and then acetylation of the fate determinant, thus controlling Gcm levels and stability over time. Defective homeostasis between the loops alters the neuron:glia ratio and freezes cells in an intermediate glial/neuronal phenotype. In sum, we identify an efficient strategy triggering cell identity, a process altered in pathological conditions such as cancer.

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Section: Discussionmentioning

confidence: 99%

Interlocked loops trigger lineage specification and stable fates in the Drosophila nervous system

et al. 2014

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“…Twist1 is an unstable protein with a half-life of ∼2 h (Lander et al, 2011). As AURKA directly phosphorylates Twist1, we hypothesized that AURKA might increase Twist1 levels by inhibiting its degradation via phosphorylation.…”

Section: Aurka Inhibits Twist1 Degradationmentioning

confidence: 99%

The Aurora-A–Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma

Wang

Nikhil

Viccaro

et al. 2017

Journal of Cell Science

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We uncovered a crucial role for the Aurora kinase A (AURKA)-Twist1 axis in promoting epithelial-to-mesenchymal transition (EMT) and chemoresistance in pancreatic cancer. Twist1 is the first EMT-specific target of AURKA that was identified using an innovative screen. AURKA phosphorylates Twist1 at three sites, which results in its multifaceted regulation -AURKA inhibits its ubiquitylation, increases its transcriptional activity and favors its homodimerization. Twist1 reciprocates and prevents AURKA degradation, thereby triggering a feedback loop. Ablation of either AURKA or Twist1 completely inhibits EMT, highlighting both proteins as central players in EMT progression. Phosphorylation-dead Twist1 serves as a dominant-negative and fully reverses the EMT phenotype induced by Twist1, underscoring the crucial role of AURKA-mediated phosphorylation in mediating Twist1-induced malignancy. Likewise, Twist1-overexpressing BxPC3 cells formed large tumors in vivo, whereas expression of phosphorylation-dead Twist1 fully abrogated this effect. Furthermore, immunohistochemical analysis of pancreatic cancer specimens revealed a 3-fold higher level of Twist1 compared to that seen in healthy normal tissues. This is the first study that links Twist1 in a feedback loop with its activating kinase, which indicates that concurrent inhibition of AURKA and Twist1 will be synergistic in inhibiting pancreatic tumorigenesis and metastasis.

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“…By adopting a mesenchymal-like morphology, disseminating cancer cells can invade the stroma by remodeling their cytoskeleton and adapting their adhesion capacities in response to the microenvironment (Grunert et al, 2003;Kopfstein and Christofori, 2006). EMT is a complex molecular process and involves the activity of numerous transcription factors (Lander et al, 2011;Mani et al, 2008;Thiery et al, 2009) that modulate cell polarity and the expression of cell-cell adhesion proteins to gain migratory and invasive properties .…”

Section: Introductionmentioning

confidence: 99%

Localized translation regulates cell adhesion and transendothelial migration

Bergeman

Caillier

Houle

et al. 2016

Journal of Cell Science

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Epithelial-to-mesenchymal transition (EMT) is a process by which cancer cells gain the ability to leave the primary tumor site and invade surrounding tissues. These metastatic cancer cells can further increase their plasticity by adopting an amoeboid-like morphology, by undergoing mesenchymal-to-amoeboid transition (MAT). We found that adhering cells produce spreading initiation centers (SICs), transient structures that are localized above nascent adhesion complexes, and share common biological and morphological characteristics associated with amoeboid cells. Meanwhile, spreading cells seem to return to a mesenchymal-like morphology. Thus, our results indicate that SIC-induced adhesion recapitulates events that are associated with amoeboid-to-mesenchymal transition (AMT). We found that polyadenylated RNAs are enriched within SICs, blocking their translation decreased adhesion potential of metastatic cells that progressed through EMT. These results point to a so-farunknown checkpoint that regulates cell adhesion and allows metastatic cells to alter adhesion strength to modulate their dissemination.

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The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1

Abstract: The core EMT regulatory factors Twist, Snail, Slug, and Sip1, while structurally diverse, are coordinately regulated by a common E3 ubiquiting ligase, Ppa.

Cited by 123 publications

References 70 publications

Interlocked loops trigger lineage specification and stable fates in the Drosophila nervous system

Interlocked loops trigger lineage specification and stable fates in the Drosophila nervous system

The Aurora-A–Twist1 axis promotes highly aggressive phenotypes in pancreatic carcinoma

Localized translation regulates cell adhesion and transendothelial migration

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