Hematopoietic cell kinase (Hck) isoforms and phagocyte duties – From signaling and actin reorganization to migration and phagocytosis

Guiet, Romain; Poincloux, Renaud; Castandet, Jérôme; Marois, Louis; Labrousse, Arnaud; Cabec, Véronique Le; Maridonneau‐Parini, Isabelle

doi:10.1016/j.ejcb.2008.03.008

Cited by 64 publications

(63 citation statements)

References 152 publications

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“…The identity of the intracellular compartments storing MMPs are poorly described in macrophages and also requires further work. We have observed that MT1-MMP does not co-localize with the lysosomal protein p61Hck (unpublished data and [60]) suggesting that macrophages could be able to secrete lysosomal proteases (cathepsins) and MMPs differentially. Actually, in tumor cells, MT1-MMP is localized in Rab8-positive exocytic vesicles which are distinct from lysosomes [84].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, these data points toward a particular involvement of lysosomal proteases in the context of the mesenchymal migration mode. Lysosomal involvement would explain why the phagocyte-specific Src tyrosine kinase Hck, which regulates the traffic of lysosomes and the formation of podosomes [59,60], controls the mesenchymal migration mode in vitro and macrophage migration in interstitial tissues in vivo [56]. In contrast with migration into cell-free matrices, macrophage infiltration inside 3D-multicellular spheroids requires MMPs and is not affected by lysosomal protease inhibitors [61].…”

Section: Role Of Proteases In 3d Migration Of Macrophagesmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Role Of Proteases In 3d Migration Of Macrophagesmentioning

confidence: 99%

Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

et al. 2011

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“…We show that the catalytic activity of p61Hck and its association with lysosomes are critical for macrophage fusion and that expression of p61Hck ca alone was sufficient to trigger the formation of MGCs. Nef is associated with lysosomes in macrophages where it colocalizes with cathepsin D. Because p61Hck activation has been associated with mobilization and exocytosis of lysosomes (29,30,47,(79)(80)(81)(82), it is conceivable that lysosomes, which contain several enzyme subsets, including proteases, hydrolases, and v-ATPase, could facilitate the cleavage of surface proteins and glycocalyx from opposite cells to interact more closely and hence facilitate cell fusion. Additionally, lysosomal proteases could modulate surface receptor activity and signaling involved in cell-cell fusion (53,68,69,(83)(84)(85).…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

Vérollet

Zhang

Cabec

et al. 2010

The Journal of Immunology

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Macrophages are a major target of HIV-1 infection. HIV-1–infected macrophages form multinucleated giant cells (MGCs) using poorly elucidated mechanisms. In this study, we show that MGC formation was reduced when human macrophages were infected with nef-deleted HIV-1. Moreover, expression of Nef, an HIV-1 protein required in several aspects of AIDS, was sufficient to trigger the formation of MGCs in RAW264.7 macrophages. Among Nef molecular determinants, myristoylation was dispensable, whereas the polyproline motif was instrumental for this phenomenon. Nef has been shown to activate hematopoietic cell kinase (Hck), a Src tyrosine kinase specifically expressed in phagocytes, through a well-described polyproline–SH3 interaction. Knockdown approaches showed that Hck is involved in Nef-induced MGC formation. Hck is expressed as two isoforms located in distinct subcellular compartments. Although both isoforms were activated by Nef, only p61Hck mediated the effect of Nef on macrophage fusion. This process was abolished in the presence of a p61Hck kinase-dead mutant or when p61Hck was redirected from the lysosome membrane to the cytosol. Finally, lysosomal proteins including vacuolar adenosine triphosphatase and proteases participated in Nef-induced giant macrophage formation. We conclude that Nef participates in HIV-1–induced MGC formation via a p61Hck- and lysosomal enzyme-dependent pathway. This work identifies for the first time actors of HIV-1–induced macrophage fusion, leading to the formation of MGCs commonly found in several organs of AIDS patients.

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“…Nevertheless, within the most differentially expressed genes in Cluster 3, we found two myeloid lineage-specific genes: the transcription factor spi1b and the granulocyte/macrophage colony-stimulating factor receptor beta (csf2rb). Other differentially expressed genes included Fc receptor gamma subunit-like ( fcer1gl), hck, a member of the Src family of tyrosine kinases mostly expressed by phagocytes in mammals and potentially implicated in signal transduction of Fc receptors and degranulation (Guiet et al 2008), complement factor B (zgc:158446), and id2 (a transcription factor interacting with spi1b) (see Fig. 3).…”

Section: Differential Expression Analysis Identifies Both Known and Nmentioning

confidence: 99%

Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immune cell types

et al. 2017

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The immune system of vertebrate species consists of many different cell types that have distinct functional roles and are subject to different evolutionary pressures. Here, we first analyzed conservation of genes specific for all major immune cell types in human and mouse. Our results revealed higher gene turnover and faster evolution of trans-membrane proteins in NK cells compared with other immune cell types, and especially T cells, but similar conservation of nuclear and cytoplasmic protein coding genes. To validate these findings in a distant vertebrate species, we used single-cell RNA sequencing of lck:GFP cells in zebrafish and obtained the first transcriptome of specific immune cell types in a nonmammalian species. Unsupervised clustering and single-cell TCR locus reconstruction identified three cell populations, T cells, a novel type of NK-like cells, and a smaller population of myeloid-like cells. Differential expression analysis uncovered new immunecell-specific genes, including novel immunoglobulin-like receptors, and neofunctionalization of recently duplicated paralogs. Evolutionary analyses confirmed the higher gene turnover of trans-membrane proteins in NK cells compared with T cells in fish species, suggesting that this is a general property of immune cell types across all vertebrates.

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Hematopoietic cell kinase (Hck) isoforms and phagocyte duties – From signaling and actin reorganization to migration and phagocytosis

Cited by 64 publications

References 152 publications

Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

Extracellular proteolysis in macrophage migration: Losing grip for a breakthrough

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

Single-cell transcriptome analysis of fish immune cells provides insight into the evolution of vertebrate immune cell types

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