KIF5B and KIF3A/KIF3B kinesins drive MT1-MMP surface exposure, CD44 shedding, and extracellular matrix degradation in primary macrophages

Wiesner, Christiane; Faix, Jan; Himmel, Mirko; Bentzien, Frank; Linder, Stefan

doi:10.1182/blood-2009-12-257089

Cited by 124 publications

(156 citation statements)

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“…It has been previously shown that tubular lysosomes undergo extension along the tracks of MTs and appear to be mediated by kinesin in murine macrophages. Later, it was shown this same phenomenon of tubular lysosomes moving along the tracks of MTs requires the motor protein kinesin (18). In this paper, we extend these kinesin studies to show an additional role in delivering key opsonin receptors, including Mac-1, to the cell surface.…”

Section: Discussionsupporting

confidence: 54%

“…We saw no obvious bundling or anomalies with the organization of MTs in the transfected cells (results not shown). We also repeated this experiment in cells transiently transfected with the YFP-Kif5B-DN rigor mutant (18) to ensure that Kif5B MT-binding activity is responsible for this observed decrease in IgG-SRBC binding. In YFP-Kif5B-DNtransfected cells, IgG-SRBC binding was reduced significantly by ∼40% (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Kinesin 5B Is Necessary for Delivery of Membrane and Receptors during FcγR-Mediated Phagocytosis

Silver

Harrison

2011

The Journal of Immunology

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FcγR-mediated phagocytosis is a cellular event that is evolutionary conserved to digest IgG-opsonized pathogens. Pseudopod formation during phagocytosis is a limiting step in managing the uptake of particles, and in this paper, we show that the conventional kinesin is involved in both receptor and membrane delivery to the phagocytic cup. Expression of a mutant kinesin isoform (GFP dominant negative mutant of kinesin H chain [EGFP-Kif5B-DN]) in RAW264.7 cells significantly reduced binding of IgG–sheep RBCs when macrophages were faced with multiple encounters with opsonized particles. Scanning electron microscopy analysis of EGFP-Kif5B-DN–expressing cells challenged with two rounds of IgG–sheep RBCs showed sparse, extremely thin pseudopods. We saw disrupted Rab11 trafficking to the phagocytic cup in EGFP-Kif5B-DN–transfected cells. Our particle overload assays also implicated phagosome membrane recycling in pseudopod formation. We observed reduced phagosome fission and trafficking in mutant kinesin-expressing cells, as well as reduced cell surface expression of FcγRs and Mac-1 receptors. In conclusion, anterograde trafficking via kinesin is essential for both receptor recycling from the phagosome and delivery of Rab11-containing membrane stores to effect broad and functional pseudopods during FcγR-mediated phagocytosis.

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Section: Discussionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Kinesin 5B Is Necessary for Delivery of Membrane and Receptors during FcγR-Mediated Phagocytosis

Silver

Harrison

2011

The Journal of Immunology

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“…As for invadopodia, the tumor cell counterpart of podosomes, a link between matrix degradation and secretion of proteases at podosomes has been described [22][23][24]. Degradation of gelatin by macrophage podosomes is MMP-dependent [5] and degradation of fibronectin or collagen I correlates with the presence of MT1-MMP (also known as MMP14) at podosomes [24,25]. MT1-MMP is involved in ECM degradation, in modulation of adhesion proteins and in proteolytic activation of MMP2.…”

Section: Introductionmentioning

confidence: 99%

Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

et al. 2011

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Macrophage tissue infiltration is a hallmark of several pathological situations including cancer, neurodegenerative disorders and chronic inflammation. Hence, deciphering the mechanisms of macrophage migration across a variety of tissues holds great potential for novel anti-inflammatory therapies. Leukocytes have long been thought to migrate through tissues by using the amoeboid (protease-independent) migration mode; however, recent evidence indicates that macrophages can use either the amoeboid or the mesenchymal (protease-dependent) migration mode depending on the environmental constraints. Proteolytic activity is required for several key processes including cell migration. Paradoxically, the role of proteases in macrophage migration has been poorly studied. Here, by focusing on the best characterized extracellular protease families -MMPs, cathepsins and urokinase-type plasminogen activator -we give an overview of their probable involvement in macrophage migration. These proteases appear to play a role in all of the situations encountered by migrating macrophages, i.e. diapedesis, 2D and 3D migration. Migration of macrophages across tissues seems to proceed through an integrative analysis of numerous environmental clues allowing the cells to adapt their migration mode (amoeboid/ mesenchymal) and secrete dedicated proteases to ensure efficient tissue infiltration, as discussed in this review. The role of proteases in macrophage migration is an emerging field of research, which deserves further work to allow a more precise understanding.Key words: Cathepsins . Macrophage . MMPs . Migration . Proteases IntroductionTrafficking of leukocytes is a key process for immune cell development and host defense (reviewed in [1]); however, the presence of phagocyte-infiltrated tissues often correlates with the aggravation of several diseases including cancers, neurodegenerative disorders, atherosclerosis and chronic inflammation.Given this, the specific targeting of phagocyte tissue infiltration, without affecting the migration of the other leukocyte subsets required for protective immunity, is a challenge for the future. The identification of the migration modes and molecular processes used by macrophages to infiltrate tissues will therefore be key for proposing new therapeutic approaches.Phagocytes are able to migrate through most tissues in the body and, in vivo, they encounter both 2-dimentional (2D) and 3-dimentional (3D) environments. 2D migration takes place along surfaces such as inner vessel walls and inner epithelial surfaces (peritoneal cavity or lung alveolae) and involves firm cell adhesion Mini-Review to the substratum. 3D migration takes place inside tissues composed of cells and extracellular matrix (ECM) components which constitute a complex and heterogeneous environment. It has been observed that for tumor cells 2D and 3D migration proceed through distinct molecular and cellular mechanisms [2,3]. Phagocyte migration in 2D and across endothelial surfaces has been studied using a large panel of in vitro model...

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“…The kinesin 2 molecular motor is known to participate to "non intraflagellar" transport in the cell, like retrograde traffic between the Golgi and the endoplasmic reticulum (ER) (Stauber et al 2006), endosome and lysosome transports (Bananis et al 2004;Brown et al 2005), endocytosis and recycling of cell surface receptors like transferrin, cubulin and megalin receptors, or of other proteins like Clc-5, the H + /Cl − exchange transporter (Schonteich et al 2008;Reed et al 2010). The KIF3 molecular motor also plays an important role in the transport of vesicles containing GluR2 and GLUT4 receptors or MT1-MMP and MMP-9 metalloproteinases from the cytosol to the plasma membrane (Imamura et al 2003;Wiesner et al 2010;Hanania et al 2012;Lin et al 2012). Unfortunately, we were unable to analyze the intracellular traffic or the cell surface expression of the TSH receptor in vivo or in vitro, due to the lack of specific antibody working on tissue sections (and probably also to the very low expression of the TSH receptor at the thyrocyte surface) and the unexpected consequence of Kif3a inactivation on TSH receptor expression directed by lentivirus infection.…”

Section: Discussionmentioning

confidence: 99%

Thyroid-specific inactivation of KIF3A alters the TSH signaling pathway and leads to hypothyroidism

D’Amico¹,

Gayral²,

Massart³

et al. 2014

EJEA

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Kinesins, including the kinesin 2/KIF3 molecular motor, play an important role in intracellular traffic and can deliver vesicles to distal axon terminal, to cilia, to non-polarized cell surface or to epithelial cell basolateral membrane, thus taking part to the establishment of cellular polarity. We report here the consequences of the kinesin 2 motor inactivation in the thyroid of 3 week-old Kif3a Δ/flox Pax8 Cre/+ mutant mice. Our results indicate first that 3 week-old Pax8 Cre/+ mice used in these experiments present minor thyroid functional defects resulting in a slight increase in circulating bioactive TSH and intracellular cAMP levels, sufficient to maintain blood T4 levels in the normal range. Second, Kif3a inactivation in thyrocytes markedly amplified the phenotype observed in Pax8 Cre/+ mice, resulting in an altered TSH signaling upstream of the second messenger cAMP and mild hypothyroidism. Finally, our results in mouse embryonic fibroblasts

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KIF5B and KIF3A/KIF3B kinesins drive MT1-MMP surface exposure, CD44 shedding, and extracellular matrix degradation in primary macrophages

Cited by 124 publications

References 53 publications

Kinesin 5B Is Necessary for Delivery of Membrane and Receptors during FcγR-Mediated Phagocytosis

Kinesin 5B Is Necessary for Delivery of Membrane and Receptors during FcγR-Mediated Phagocytosis

Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

Thyroid-specific inactivation of KIF3A alters the TSH signaling pathway and leads to hypothyroidism

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