α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3

Paul, Nikki R.; Allen, Jennifer L.; Chapman, Anna; Morlan-Mairal, Maria; Zindy, Egor; Jacquemet, Guillaume; Ama, Laura Fernandez del; Ferizovic, Nermina; Green, David; Howe, Jonathan D.; Ehler, Elisabeth; Hurlstone, Adam; Caswell, Patrick T.

doi:10.1083/jcb.201502040

Cited by 98 publications

(100 citation statements)

References 85 publications

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“…These differences may also be mediated by variations in upstream regulators of ROCK such as podoplanin and the different Rho GTPases as well as other pathways downstream of ROCK that include ezrin and moesin that also regulate invadopodia [53, 85, 102–104]. In particular, RhoA is known to regulate force sensing pathways including actomyosin contractility [105–107] as well as invasive migration and/or metastasis by cancer cells [108–110], while RhoC has been found to promote invadopodia activity locally through the LIMK-cofilin pathway [17, 34, 85]. Furthermore, podoplanin mediates ECM degradation by invadopodia through a ROCK-LIMK-cofilin pathway that is regulated by RhoC [104].…”

Section: Discussionmentioning

confidence: 99%

Matrix rigidity differentially regulates invadopodia activity through ROCK1 and ROCK2

Jerrell

Parekh

2016

Biomaterials

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ROCK activity increases due to ECM rigidity in the tumor microenvironment and promotes a malignant phenotype via actomyosin contractility. Invasive migration is facilitated by actin-rich adhesive protrusions known as invadopodia that degrade the ECM. Invadopodia activity is dependent on matrix rigidity and contractile forces suggesting that mechanical factors may regulate these subcellular structures through ROCK-dependent actomyosin contractility. However, emerging evidence indicates that the ROCK1 and ROCK2 isoforms perform different functions in cells suggesting that alternative mechanisms may potentially regulate rigidity-dependent invadopodia activity. In this study, we found that matrix rigidity drives ROCK signaling in cancer cells but that ROCK1 and ROCK2 differentially regulate invadopodia activity through separate signaling pathways via contractile (NM II) and non-contractile (LIMK) mechanisms. These data suggest that the mechanical rigidity of the tumor microenvironment may drive ROCK signaling through distinct pathways to enhance the invasive migration required for cancer progression and metastasis.

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Section: Discussionmentioning

confidence: 99%

Matrix rigidity differentially regulates invadopodia activity through ROCK1 and ROCK2

Jerrell

Parekh

2016

Biomaterials

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“…Integrin dynamics has been the focus of intense investigation with particular attention from investigators in the fields of cancer cell metastasis, and angiogenesis (De Franceschi et al, 2015; Caswell et al, 2007; Dozynkiewicz et al, 2012; Paul et al, 2015; Tian et al, 2012). Interestingly, Rab22A also contributes to exosome biogenesis and shedding from primary tumor cells and tumor metastasis (Wang et al, 2014b).…”

Section: Discussionmentioning

confidence: 99%

Ankyrin-B is a PI3P effector that promotes polarized α5β1-integrin recycling via recruiting RabGAP1L to early endosomes

Lorenzo

King

et al. 2016

eLife

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Endosomal membrane trafficking requires coordination between phosphoinositide lipids, Rab GTPases, and microtubule-based motors to dynamically determine endosome identity and promote long-range organelle transport. Here we report that ankyrin-B (AnkB), through integrating all three systems, functions as a critical node in the protein circuitry underlying polarized recycling of α5β1-integrin in mouse embryonic fibroblasts, which enables persistent fibroblast migration along fibronectin gradients. AnkB associates with phosphatidylinositol 3-phosphate (PI3P)-positive organelles in fibroblasts and binds dynactin to promote their long-range motility. We demonstrate that AnkB binds to Rab GTPase Activating Protein 1-Like (RabGAP1L) and recruits it to PI3P-positive organelles, where RabGAP1L inactivates Rab22A, and promotes polarized trafficking to the leading edge of migrating fibroblasts. We further determine that α5β1-integrin depends on an AnkB/RabGAP1L complex for polarized recycling. Our results reveal AnkB as an unexpected key element in coordinating polarized transport of α5β1-integrin and likely of other specialized endocytic cargos.DOI: http://dx.doi.org/10.7554/eLife.20417.001

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“…Similar to lamellipodia on 2D surfaces, these protrusions use polarized Rac1 activity to direct Arp2/3-mediated actin-polymerization and push their plasma membrane through the matrix [31,36]. In contrast to lobopodial fibroblasts, intracellular pressure is lower and uniform throughout these cells.…”

Section: Actin Polymerization-driven Membrane Protrusionmentioning

confidence: 99%

“…Normally, these cells utilize Arp2/3 to form lamellipodial protrusions in fibronectin-rich 3D collagen gels [36]. When Arp2/3 is inhibited, either directly or through increased α5β1 integrin recycling, these cells switch to using RhoA and the formin FHOD3 to help form distinctive spikes of F-actin at their leading edge.…”

Section: Actin Polymerization-driven Membrane Protrusionmentioning

confidence: 99%

Multiple mechanisms of 3D migration: the origins of plasticity

Petrie

Yamada

2016

Current Opinion in Cell Biology

122

102

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Cells migrate through 3D environments using a surprisingly wide variety of molecular mechanisms. These distinct modes of migration often rely on the same intracellular components, which are used in different ways to achieve cell motility. Recent work reveals that how a cell moves can be dictated by the relative amounts of cell-matrix adhesion and actomyosin contractility. A current concept is that the level of difficulty in squeezing the nucleus through a confining 3D environment determines the amounts of adhesion and contractility required for cell motility. Ultimately, determining how the nucleus controls the mode of cell migration will be essential for understanding both physiological and pathological processes dependent on cell migration in the body.

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α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3

Abstract: Rab-coupling protein–mediated integrin trafficking promotes filopodia formation via RhoA-ROCK-FHOD3, generating non-lamellipodial actin spike protrusions that drive cancer cell migration in 3D extracellular matrix and in vivo.

Cited by 98 publications

References 85 publications

Matrix rigidity differentially regulates invadopodia activity through ROCK1 and ROCK2

Matrix rigidity differentially regulates invadopodia activity through ROCK1 and ROCK2

Ankyrin-B is a PI3P effector that promotes polarized α5β1-integrin recycling via recruiting RabGAP1L to early endosomes

Multiple mechanisms of 3D migration: the origins of plasticity

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