A NUMB–EFA6B–ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility

Zobel, Martina; Disanza, Andrea; Senic-Matuglia, Francesca; Franco, Michel; Colaluca, Ivan N.; Confalonieri, Stefano; Bisi, Sara; Barbieri, Elisa; Caldieri, Giusi; Sigismund, Sara; Pece, Salvatore; Chavrier, Philippe; Fiore, Pier Paolo Di; Scita, Giorgio

doi:10.1083/jcb.201802023

Cited by 20 publications

(21 citation statements)

References 84 publications

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“…Thus, EFA6B depletion in both luminal and basal cells induces EMT and stimulates collective invasion. In agreement with our results, it was recently reported that the endocytic protein NUMB inhibits the acquisition of migratory and invasive properties by activating EFA6B/ARF6 in response to growth factors 36 .…”

Section: Emtsupporting

confidence: 94%

EFA6B regulates a stop signal for collective invasion in breast cancer

Fayad

Monserrat

Partisani

et al. 2020

Preprint

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Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes, however additional mutations provide selective advantages to the tumor cells to resist treatment and develop metastases, therefore identification of secondary mutations is of paramount importance. EFA6B (Exchange Factor for ARF6, B) expression is reduced in breast cancer. To study the pro-tumoral impact of the loss of EFA6B we have invalidated its gene in normal human mammary cells. We found that EFA6B knock-out triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal a new EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up new avenues for the treatment of invasive breast cancer.

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Section: Emtsupporting

confidence: 94%

EFA6B regulates a stop signal for collective invasion in breast cancer

Fayad

Monserrat

Partisani

et al. 2020

Preprint

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“…While this finding is well in line with a function of Numb as endocytic adaptor, its impact on Notch signaling appears to be more complex since Numb was also reported to influence the postendocytic trafficking [269] and degradation of Notch [33] as well as its ligand Dll4 [270]. In fact, Numb has been shown to interact not only with endocytic proteins and cargo, but also with components of the recycling machinery such as EFA6B-Arf6 [271] and EHD proteins [272] and with Ubiquitin ligases [33], and is implicated in the sorting of proteins such as N-cadherin [273] and APP [274].…”

Section: Insights Into Numb Function From D Melanogastermentioning

confidence: 63%

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

Tehran

López-Hernández

Maritzen

2019

Cells

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Cells need to exchange material and information with their environment. This is largely achieved via cell-surface receptors which mediate processes ranging from nutrient uptake to signaling responses. Consequently, their surface levels have to be dynamically controlled. Endocytosis constitutes a powerful mechanism to regulate the surface proteome and to recycle vesicular transmembrane proteins that strand at the plasma membrane after exocytosis. For efficient internalization, the cargo proteins need to be linked to the endocytic machinery via adaptor proteins such as the heterotetrameric endocytic adaptor complex AP-2 and a variety of mostly monomeric endocytic adaptors. In line with the importance of endocytosis for nutrient uptake, cell signaling and neurotransmission, animal models and human mutations have revealed that defects in these adaptors are associated with several diseases ranging from metabolic disorders to encephalopathies. This review will discuss the physiological functions of the so far known adaptor proteins and will provide a comprehensive overview of their links to human diseases.

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“…Finally, we calculated a cell elongation index (the ratio between the major and minor axis of cell, Fig EV7D) which directly correlates with mesenchymal migration, a specific mode of cell locomotion through the ECM, associated with CDR-dependent matrix invasion (Hoon et al, 2012;Suetsugu et al, 2003;Zobel et al, 2018). We found that the cell elongation index of GAS6-stimulated cells forming CDRs was significantly higher in comparison to nonstimulated cells ( Fig 6I, Fig EV7D).…”

Section: Gas6-axl-induced Cdrs Are Involved In Fa Disassemblymentioning

confidence: 92%

GAS6-AXL signaling triggers actin remodeling and macropinocytosis that drive cancer cell invasion

Zdżalik-Bielecka

Poświata

Kozik

et al. 2020

Preprint

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AXL, a member of the TAM (TYRO3, AXL, MER) receptor tyrosine kinase family, and its ligand GAS6 are implicated in oncogenesis and metastasis of many cancer types. However, the exact cellular processes activated by GAS6-AXL remain largely unexplored. Here, we identified an interactome of AXL and revealed its associations with proteins regulating actin dynamics. Consistently, GAS6-mediated AXL activation triggered actin remodeling manifested by peripheral membrane ruffling and circular dorsal ruffles (CDRs). This further promoted macropinocytosis that mediated the internalization of GAS6-AXL complexes and sustained survival of glioblastoma cells grown under glutamine-deprived conditions. GAS6induced CDRs contributed to focal adhesion (FA) turnover, cell spreading and elongation.Consequently, AXL activation by GAS6 drove invasion of cancer cells in a spheroid model.All these processes required the kinase activity of AXL but not TYRO3, and downstream activation of PI3K. We propose that GAS6-AXL signaling induces multiple actin-driven cytoskeletal rearrangements and macropinocytosis that jointly contribute to cancer cell invasion.

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A NUMB–EFA6B–ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility

Cited by 20 publications

References 84 publications

EFA6B regulates a stop signal for collective invasion in breast cancer

EFA6B regulates a stop signal for collective invasion in breast cancer

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

GAS6-AXL signaling triggers actin remodeling and macropinocytosis that drive cancer cell invasion

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