Re-arrangements of podosome structures are observed when Hck is activated in myeloid cells

Poincloux, Renaud; Vincent, Claire; Labrousse, Arnaud; Castandet, Jérôme; Rigo, Maxime; Cougoule, Céline; Bordier, Cécile; Cabec, Véronique Le; Maridonneau‐Parini, Isabelle

doi:10.1016/j.ejcb.2005.09.012

Cited by 37 publications

(39 citation statements)

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“…2 show that Sos1 silencing results in alteration of macrophage cytoskeleton dynamics similar to those reported in cells where Abl, or Src-family kinases, were deficient or inhibited (14,15,18). The established relation among Abl, Src, and Rac in different cell context (17,28,36,(40)(41)(42)(43) prompted experiments to address whether Sos1 silencing affects Rac activation.…”

Section: Sos1 Regulates Cytoskeleton Dynamics In Macrophagesmentioning

confidence: 99%

“…The myeloid leukocyte-specific Src-family kinase member Hck has been demonstrated to regulate podosome formation and podosomedependent ECM degradation (8,14,15), an action that may in part depend on its capability to phosphorylate the Wiskott-Aldrich syndrome protein (16). In addition, we reported that the cytoplasmic tyrosine kinase Abl, which forms a tripartite complex with the Src kinases Hck or Fgr bound to integrins (17), redistributes to podosomes, and its silencing or pharmacologic inhibition results in podosome disassembly and reduction of macrophage threedimensional migration and ECM degradative capacity (18).…”

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Sos1 Regulates Macrophage Podosome Assembly and Macrophage Invasive Capacity

Baruzzi

Remelli

Lorenzetto

et al. 2015

The Journal of Immunology

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Podosomes are protrusive structures implicated in macrophage extracellular matrix degradation and three-dimensional migration through cell barriers and the interstitium. Podosome formation and assembly are regulated by cytoskeleton remodeling requiring cytoplasmic tyrosine kinases of the Src and the Abl families. Considering that Abl has been reported to phosphorylate the guanine nucleotide exchange factor Sos1, eliciting its Rac-guanine nucleotide exchange factor activity, and Rac regulates podosome formation in myeloid cells and invadopodia formation in cancer cells, we addressed whether Sos1 is implicated in podosome formation and function in macrophages. We found that ectopically expressed Abl or the Src kinase Fgr phosphorylate Sos1, and the Src kinases Hck and Fgr are required for Abl and Sos1 phosphorylation and Abl/Sos1 interaction in macrophages. Sos1 localizes to podosomes in both murine and human macrophages, and its silencing by small interfering RNA results in disassembly of murine macrophage podosomes and a marked reduction of GTP loading on Rac. Matrix degradative capacity, three-dimensional migration through Matrigel, and transmigration through an endothelial cell monolayer of Sos1-silenced macrophages were inhibited. In addition, Sos1- or Abl-silenced macrophages, or macrophages treated with the selective Abl inhibitor imatinib mesylate had a reduced capability to migrate into breast tumor spheroids, the majority of cells remaining at the margin and the outer layers of the spheroid itself. Because of the established role of Src and Abl kinases to regulate also invadopodia formation in cancer cells, our findings suggest that targeting the Src/Abl/Sos1/Rac pathway may represent a double-edged sword to control both cancer-invasive capacities and cancer-related inflammation.

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Section: Sos1 Regulates Cytoskeleton Dynamics In Macrophagesmentioning

confidence: 99%

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confidence: 99%

Sos1 Regulates Macrophage Podosome Assembly and Macrophage Invasive Capacity

Baruzzi

Remelli

Lorenzetto

et al. 2015

The Journal of Immunology

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“…In macrophages, p61Hck also localizes to podosomes, which are actin-rich adhesive structures that are associated with protease activity. Overexpression of a constitutively active form of p61Hck leads to the formation of podosome clusters or rosettes (26,27 RNAi-mediated knockdown of SFKs and their regulators has been used to dissect the roles of these kinases in various signaling pathways. Adachi et al describe siRNA specific for Hck, Fgr or Lyn that were used to study complement-mediated phagocytosis (37) (see section 3.2.2), and siRNA specific for Csk has been used to assess SFK function downstream of Toll-like receptor (TLR) signaling in macrophages (38) (see section 3.3.1).…”

Section: Many Substrates Of Sfks Have Been Identified (7)mentioning

confidence: 99%

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The diverse functions of Src family kinases in macrophages

Abram

Lowell²

2008

Front Biosci

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Macrophages are key components of the innate immune response. These cells possess a diverse repertoire of receptors that allow them to respond to a host of external stimuli including cytokines, chemokines, and pathogen-associated molecules. Signals resulting from these stimuli activate a number of macrophage functional responses such as adhesion, migration, phagocytosis, proliferation, survival, cytokine release and production of reactive oxygen and nitrogen species. The cytoplasmic tyrosine kinase Src and its family members (SFKs) have been implicated in many intracellular signaling pathways in macrophages, initiated by a diverse set of receptors ranging from integrins to Toll-like receptors. However, it has been difficult to implicate any given member of the family in any specific pathway. SFKs appear to have overlapping and complementary functions in many pathways. Perhaps the function of these enzymes is to modulate the overall intracellular signaling network in macrophages, rather than operating as exclusive signaling switches for defined pathways. In general, SFKs may function more like rheostats, influencing the amplitude of many pathways. KeywordsTyrosine kinases; signal transduction; innate immunity; integrins; Toll-like receptors; ITIM; ITAM; adhesion; migration; Hck; Fgr; Lyn; Review INTRODUCTION Src family kinases -general approachesc-Src was first described as the cellular counterpart of v-Src, the transforming gene found in Rous Sarcoma Virus, and has since been the focus of much research. Src and its other family members, referred to as Src Family Kinases (SFKs) throughout this review, have been implicated in many diverse signaling pathways in both immune (1) and non-immune cell types (2). This is apparent from the close to 25,000 PubMed hits one gets when researching these enzymes. Furthermore, a strong clinical interest has developed in SFKs based on the growing realization of their central roles in human cancer (3, 4).Src family members include c-Src, Fyn, c-Yes, Lck, Hck, c-Fgr, Lyn, Blk, and Yrk. Src, Fyn and Yes are ubiquitously expressed whereas Lck, Hck, Fgr, Lyn and Blk tend to be more restricted to cells of hematopoietic origin. Yrk has only been found in chickens. The SFKs Send correspondence to: Dr Clifford Lowell, Department of Laboratory Medicine, University of California, San Francisco, S1058, 513 Parnassus Avenue, San Francisco, CA94143-0451, Tel: 415-476-2540, Fax: 415-502-9404, clifford.lowell@ucsf.edu. HHS Public AccessAuthor manuscript Front Biosci. Author manuscript; available in PMC 2015 June 05. Published in final edited form as:Front Biosci. ; 13: 4426-4450. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript are cytoplasmic tyrosine kinases, consisting of an N-terminal unique domain, a Src homology 3 (SH3) domain that can interact with polyproline-rich motifs, a Src homology 2 (SH2) domain that binds phosphotyrosine residues, and a tyrosine kinase domain ( Figure 1A). Acylation of SFKs at their N-terminus (palmitoylation and/or myristoylation) al...

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“…Podosomes are very dynamic structures that present a rapid actin turnover, with a lifespan ranging from 2 to 14 min (6,7). When macrophages are activated, their podosomes can rearrange in a particular belt-shape structure called a rosette that efficiently degrades the ECM (1,8). Works on proteasedependent 3D migration of macrophages indicate that podosomes are key elements of this process (1,9) and correspond to actin-rich protrusive structures invading the ECM (2, 10).…”

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Dynamics of podosome stiffness revealed by atomic force microscopy

Labernadie

Thibault

Vieu

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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163

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Podosomes are unique cellular entities specifically found in macrophages and involved in cell-matrix interactions, matrix degradation, and 3D migration. They correspond to a core of F-actin surrounded at its base by matrix receptors. To investigate the structure/function relationships of podosomes, soft lithography, atomic force microscopy (AFM), and correlative fluorescence microscopy were used to characterize podosome physical properties in macrophages differentiated from human blood monocytes. Podosome formation was restricted to delineated areas with micropatterned fibrinogen to facilitate AFM analyses. Podosome height and stiffness were measured with great accuracy in living macrophages (578 ± 209 nm and 43.8 ± 9.3 kPa) and these physical properties were independent of the nature of the underlying matrix. In addition, time-lapse AFM revealed that podosomes harbor two types of overlapping periodic stiffness variations throughout their lifespan, which depend on F-actin and myosin II activity. This report shows that podosome biophysical properties are amenable to AFM, allowing the study of podosomes in living macrophages at nanoscale resolution and the analysis of their intimate dynamics. Such an approach opens up perspectives to better understand the mechanical functionality of podosomes under physiological and pathological contexts.cytoskeleton | Young's modulus | microcontact printing

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Re-arrangements of podosome structures are observed when Hck is activated in myeloid cells

Cited by 37 publications

References 20 publications

Sos1 Regulates Macrophage Podosome Assembly and Macrophage Invasive Capacity

Sos1 Regulates Macrophage Podosome Assembly and Macrophage Invasive Capacity

The diverse functions of Src family kinases in macrophages

Dynamics of podosome stiffness revealed by atomic force microscopy

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