A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination

Frittoli, Emanuela; Palamidessi, Andrea; Marighetti, Paola; Confalonieri, Stefano; Bianchi, Fabrizio; Malinverno, Chiara; Mazzarol, Giovanni; Viale, Giuseppe; Martín‐Padura, Inés; Garrè, M.; Parazzoli, Dario; Mattei, Valentina Di; Cortellino, Salvatore; Bertalot, Giovanni; Fiore, Pier Paolo Di; Scita, Giorgio

doi:10.1083/jcb.201403127

Cited by 122 publications

(168 citation statements)

References 64 publications

(97 reference statements)

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“…Notably, overexpression of Rab5 in cancer cells was found to be necessary and sufficient for cell invasion and tumor dissemination by enhancing MT1-MMP driven extracellular matrix degradation and increasing intratumoral cell motility [118]. Finally, in vitro data provide evidence that extracellular matrix proteins, such as fibronectin, collagen and fragments thereof, themselves are able to influence integrin recycling and regulate gene expression of MMPs (e.g.…”

Section: Trafficking Of Other Cell Surface Adhesions Proteinsmentioning

confidence: 94%

“…Delivery of MT1-MMP to the invadosome further requires the master regulators of endocytosis Rab5 and Rab4 [118], as well as a vSNARE and VAMP7 for fusing the MT1-MMP-containing vesicles with the plasma membrane and presumably Rab8 for exocytosis [119]. Notably, overexpression of Rab5 in cancer cells was found to be necessary and sufficient for cell invasion and tumor dissemination by enhancing MT1-MMP driven extracellular matrix degradation and increasing intratumoral cell motility [118].…”

Section: Trafficking Of Other Cell Surface Adhesions Proteinsmentioning

confidence: 99%

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On the move: endocytic trafficking in cell migration

Maritzen

Schachtner

Legler

2015

Cell. Mol. Life Sci.

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Directed cell migration is a fundamental process underlying diverse physiological and pathophysiological phenomena ranging from wound healing and induction of immune responses to cancer metastasis. Recent advances reveal that endocytic trafficking contributes to cell migration in multiple ways. (1) At the level of chemokines and chemokine receptors: internalization of chemokines by scavenger receptors is essential for shaping chemotactic gradients in tissue, whereas endocytosis of chemokine receptors and their subsequent recycling is key for maintaining a high responsiveness of migrating cells. (2) At the level of integrin trafficking and focal adhesion dynamics: endosomal pathways do not only modulate adhesion by delivering integrins to their site of action, but also by supplying factors for focal adhesion disassembly. (3) At the level of extracellular matrix reorganization: endosomal transport contributes to tumor cell migration not only by targeting integrins to invadosomes but also by delivering membrane type 1 matrix metalloprotease to the leading edge facilitating proteolysis-dependent chemotaxis. Consequently, numerous endocytic and endosomal factors have been shown to modulate cell migration. In fact key modulators of endocytic trafficking turn out to be also key regulators of cell migration. This review will highlight the recent progress in unraveling the contribution of cellular trafficking pathways to cell migration.

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Section: Trafficking Of Other Cell Surface Adhesions Proteinsmentioning

confidence: 94%

Section: Trafficking Of Other Cell Surface Adhesions Proteinsmentioning

confidence: 99%

On the move: endocytic trafficking in cell migration

Maritzen

Schachtner

Legler

2015

Cell. Mol. Life Sci.

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“…Moreover, MT1-MMP in conjunction with the physical properties of ECM is a determining factor in mesenchymal cell migration in 3D (Wolf et al, 2013). MT1-MMP trafficking and delivery to the plasma membrane are microtubule dependent, involve late endosomes and are required for mesenchymal invasion by cancer cells (Frittoli et al, 2014;Macpherson et al, 2014;Remacle et al, 2005;Rosse et al, 2014). It should be noted that delivery of MT1-MMP to the plasma membrane is also controlled by F-actin and its regulator N-WASP (Yu et al, 2012), and the respective contributions of microtubule-and actin-based mechanisms of MT1-MMP trafficking in 3D will thus have to be further investigated.…”

Section: Ecm Adhesion and Trafficking In 3d Environmentsmentioning

confidence: 99%

Microtubules in 3D cell motility

Bouchet

Akhmanova

2017

Journal of Cell Science

102

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Three-dimensional (3D) cell motility underlies essential processes, such as embryonic development, tissue repair and immune surveillance, and is involved in cancer progression. Although the cytoskeleton is a well-studied regulator of cell migration, most of what we know about its functions originates from studies conducted in twodimensional (2D) cultures. This research established that the microtubule network mediates polarized trafficking and signaling that are crucial for cell shape and movement in 2D. In parallel, developments in light microscopy and 3D cell culture systems progressively allowed to investigate cytoskeletal functions in more physiologically relevant settings. Interestingly, several studies have demonstrated that microtubule involvement in cell morphogenesis and motility can differ in 2D and 3D environments. In this Commentary, we discuss these differences and their relevance for the understanding the role of microtubules in cell migration in vivo. We also provide an overview of microtubule functions that were shown to control cell shape and motility in 3D matrices and discuss how they can be investigated further by using physiologically relevant models.

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“…As a model system, we study doxycycline-inducible, RAB5A-expressing populations of human mammary epithelial MCF-10A cells. RAB5A is a master regulator of the endocytic activity of the cell and it plays an important role in the dissemination of aggressive breast tumours [38,39,40]. In control monolayers, cell density increases due to mitotic division, which causes a near complete kinetic arrest akin to a jamming or rigidity transition [32,41].…”

Section: Introductionmentioning

confidence: 99%

Giant fluctuations and structural effects in a flocking epithelium

Giavazzi¹,

Malinverno²,

Corallino³

et al. 2017

J. Phys. D: Appl. Phys.

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Abstract. Epithelial cells cultured in a monolayer are very motile in isolation but reach a near-jammed state when mitotic division increases their number above a critical threshold. We have recently shown that a monolayer can be reawakened by over-expression of a single protein, RAB5A, a master regulator of endocytosis. This reawakening of motility was explained in term of a flocking transition that promotes the emergence of a large-scale collective migratory pattern. Here we focus on the impact of this reawakening on the structural properties of the monolayer. We find that the unjammed monolayer is characterised by a fluidisation at the single cell level and by enhanced non-equilibrium large-scale number fluctuations at a larger length scale. Also with the help of numerical simulations, we trace back the origin of these fluctuations to the selfpropelled active nature of the constituents and to the existence of a local alignment mechanism, leading to the spontaneous breaking of the orientational symmetry.

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A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination

Abstract: RAB5A and RAB4 promote breast tumor cell dissemination by controlling the trafficking of proteins necessary for localized invadosome formation.

Cited by 122 publications

References 64 publications

On the move: endocytic trafficking in cell migration

On the move: endocytic trafficking in cell migration

Microtubules in 3D cell motility

Giant fluctuations and structural effects in a flocking epithelium

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