N-WASP coordinates the delivery and F-actin–mediated capture of MT1-MMP at invasive pseudopods

Yu, Xinzi; Zech, Tobias; McDonald, Laura; González, Esther G.; Li, Ang; Macpherson, Iain; Schwarz, Juliane P.; Spence, Heather J.; Futó, Kinga; Timpson, Paul; Nixon, Colin; Ma, Yafeng; Antón, Inés M.; Visegrády, Balázs; Insall, Robert H.; Oien, Karin A.; Blyth, Karen; Norman, Jim C.; Machesky, Laura M.

doi:10.1083/jcb.201203025

Cited by 153 publications

(223 citation statements)

References 66 publications

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“…Third, SNX9 functions in MT1-MMP endocytosis and hence can regulate invadopodia function. As TKS5 and SNX9 are preferentially localized at the tip of invadopodia where MT1-MMP is also concentrated (Yu et al, 2012), TKS5 might locally interfere with SNX9 function in CME to stabilize MT1-MMP at these structures. GAPDH was used as loading control in A,B.…”

Section: Discussionmentioning

confidence: 99%

Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells

Bendris

Stearns

Reis

et al. 2016

Journal of Cell Science

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The ability of cancer cells to degrade the extracellular matrix and invade interstitial tissues contributes to their metastatic potential. We recently showed that overexpression of sorting nexin 9 (SNX9) leads to increased cell invasion and metastasis in animal models, which correlates with increased SNX9 protein expression in metastases from human mammary cancers. Here, we report that SNX9 expression is reduced relative to neighboring normal tissues in primary breast tumors, and progressively reduced in more aggressive stages of non-small-cell lung cancers. We show that SNX9 is localized at invadopodia where it directly binds the invadopodia marker TKS5 and negatively regulates invadopodia formation and function. SNX9 depletion increases invadopodia number and the local recruitment of MT1-MMP by decreasing its internalization. Together, these effects result in increased localized matrix degradation. We further identify SNX9 as a Src kinase substrate and show that this phosphorylation is important for SNX9 activity in regulating cell invasion, but is dispensable for its function in regulating invadopodia. The diversified changes associated with SNX9 expression in cancer highlight its importance as a central regulator of cancer cell behavior.

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Section: Discussionmentioning

confidence: 99%

Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells

Bendris

Stearns

Reis

et al. 2016

Journal of Cell Science

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“…Cancer cells were shown to coordinate mechanotransduction and extracellular matrix remodeling by segregating the anterior force-generating leading edge containing integrins, F-actin and the membrane type 1 (MT1)-MMP from the posterior proteolytic zone where extracellular matrix fibers are cleaved [116]. Of note, the delivery of MT1-MMP to the leading invasive pseudopods of a migrating cell is coordinated by the NPF Neural Wiskott Aldrich syndrome protein (N-WASP) [117]. N-WASP is upregulated in invasive cancer cells and promotes the trafficking of MT1-MMP from late endosomes to the plasma membrane where it stabilizes MMT1-MMP via direct tethering of its cytoplasmic tail to F-actin [117].…”

Section: Trafficking Of Other Cell Surface Adhesions Proteinsmentioning

confidence: 99%

“…Of note, the delivery of MT1-MMP to the leading invasive pseudopods of a migrating cell is coordinated by the NPF Neural Wiskott Aldrich syndrome protein (N-WASP) [117]. N-WASP is upregulated in invasive cancer cells and promotes the trafficking of MT1-MMP from late endosomes to the plasma membrane where it stabilizes MMT1-MMP via direct tethering of its cytoplasmic tail to F-actin [117].…”

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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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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“…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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N-WASP coordinates the delivery and F-actin–mediated capture of MT1-MMP at invasive pseudopods

Abstract: N-WASP is critical for cancer cell invasion through its promotion of the trafficking and capture of MT1-MMP in invasive pseudopods.

Cited by 153 publications

References 66 publications

Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells

Sorting nexin 9 negatively regulates invadopodia formation and function in cancer cells

On the move: endocytic trafficking in cell migration

Microtubules in 3D cell motility

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