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The Journal of Cell Biology Jan 2017Podosomes are actin-based proteolytic microdomains of the plasma membrane found in cells that travel across tissues. In this issue, Rafiq et al. (2017. J. Cell Biol....
Podosomes are actin-based proteolytic microdomains of the plasma membrane found in cells that travel across tissues. In this issue, Rafiq et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201605104) reveal that the small guanosine triphosphatase ARF1, a well-known orchestrator of membrane traffic at the Golgi, regulates podosome formation, maintenance, and function.
Topics: Actins; Cell Membrane; Golgi Apparatus; Humans; Podosomes; Protein Transport
PubMed: 28007918
DOI: 10.1083/jcb.201611097 -
Scientific Reports Sep 2017The clinical significance of STIM proteins and Orai Ca channels in tumor progression has been demonstrated in different types of cancers. Podosomes are dynamic...
The clinical significance of STIM proteins and Orai Ca channels in tumor progression has been demonstrated in different types of cancers. Podosomes are dynamic actin-rich cellular protrusions that facilitate cancer cell invasiveness by degrading extracellular matrix. Whether STIM1-dependent Ca signaling facilitates cancer cell invasion through affecting podosome formation remains unclear. Here we show that the invasive fronts of cancer tissues overexpress STIM1, accompanied by active store-operated Ca entry (SOCE). Interfering SOCE activity by SOCE inhibitors and STIM1 or Orai1 knockdown remarkably affects podosome rosettes formation. Mechanistically, STIM1-silencing significantly alters the podosome rosettes dynamics, shortens the maintenance phase of podosome rosettes and reduces cell invasiveness. The subsequently transient expression of STIM1 cDNA in STIM1-null (STIM1) mouse embryo fibroblasts rescues the suppression of podosome formation, suggesting that STIM1-mediated SOCE activation directly regulates podosome formation. This study uncovers SOCE-mediated Ca microdomain that is the molecular basis for Ca sensitivity controlling podosome formation.
Topics: Animals; Calcium; Cations, Divalent; Cell Proliferation; Female; Humans; Mice; Podosomes; Signal Transduction; Stromal Interaction Molecule 1; Tumor Cells, Cultured
PubMed: 28912430
DOI: 10.1038/s41598-017-11273-2 -
International Journal of Molecular... Nov 2021Currently, the etiology of many neuromuscular disorders remains unknown. Many of them are characterized by aberrations in the maturation of the neuromuscular junction...
Currently, the etiology of many neuromuscular disorders remains unknown. Many of them are characterized by aberrations in the maturation of the neuromuscular junction (NMJ) postsynaptic machinery. Unfortunately, the molecular factors involved in this process are still largely unknown, which poses a great challenge for identifying potential therapeutic targets. Here, we identified Tks5 as a novel interactor of αdystrobrevin-1, which is a crucial component of the NMJ postsynaptic machinery. Tks5 has been previously shown in cancer cells to be an important regulator of actin-rich structures known as invadosomes. However, a role of this scaffold protein at a synapse has never been studied. We show that Tks5 is crucial for remodeling of the NMJ postsynaptic machinery by regulating the organization of structures similar to the invadosomes, known as synaptic podosomes. Additionally, it is involved in the maintenance of the integrity of acetylcholine receptor (AChR) clusters and regulation of their turnover. Lastly, our data indicate that these Tks5 functions may be mediated by its involvement in recruitment of actin filaments to the postsynaptic machinery. Collectively, we show for the first time that the Tks5 protein is involved in regulation of the postsynaptic machinery.
Topics: Animals; Cells, Cultured; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Neuromuscular Junction; Phosphate-Binding Proteins; Podosomes; Post-Synaptic Density; RNA, Small Interfering; Synapses
PubMed: 34769479
DOI: 10.3390/ijms222112051 -
Biochimica Et Biophysica Acta.... Jun 2023Alzheimer's disease (AD) is a progressive neurodegenerative disease that is associated with protein misfolding, plaque accumulation, neuronal dysfunction, synaptic loss,...
Alzheimer's disease (AD) is a progressive neurodegenerative disease that is associated with protein misfolding, plaque accumulation, neuronal dysfunction, synaptic loss, and cognitive decline. The pathological cascade of AD includes the intracellular Tau hyperphosphorylation and its subsequent aggregation, extracellular Amyloid-β plaque formation and microglia-mediated neuroinflammation. The extracellular release of aggregated Tau is sensed by surveilling microglia through the involvement of various cell surface receptors. Among all, purinergic P2Y12R signaling is involved in microglial chemotaxis towards the damaged neurons. Microglial migration is highly linked with membrane-associated actin remodeling leading to the phagocytosis of extracellular Tau species. Here, we studied the formation of various actin structures such as podosome, lamellipodia and filopodia, in response to extracellular Tau monomers and aggregates. Microglial podosomes are colocalized with actin nucleator protein WASP, Arp2 and TKS5 adaptor protein during Tau-mediated migration. Moreover, the P2Y12 receptors were associated with F-actin-rich podosome structures, which signify the potential of Tau aggregates in microglial chemotaxis through the involvement of actin remodeling.
Topics: Humans; Microglia; Actins; Podosomes; Receptors, Purinergic P2Y12; Neurodegenerative Diseases; Alzheimer Disease
PubMed: 37061007
DOI: 10.1016/j.bbamcr.2023.119477 -
Genes Jan 2022Frank-Ter Haar syndrome (FTHS), sometimes referred to as Ter Haar syndrome, is a rare hereditary disorder that manifests in skeletal, cardiac, and ocular anomalies,...
Frank-Ter Haar syndrome (FTHS), sometimes referred to as Ter Haar syndrome, is a rare hereditary disorder that manifests in skeletal, cardiac, and ocular anomalies, including hypertelorism, glaucoma, prominent eyes, and facial abnormalities. In this study, we performed whole-exome sequencing (WES) to identify the genetic component responsible for the phenotype of the index patient, a male infant born to a consanguineous family from Saudi Arabia. The analysis revealed a homozygous missense variant, c.280C>G, in the SH3PXD2B gene, which cosegregates with the familial phenotype with a plausible autosomal-recessive mode of inheritance, indicating a potential disease-causing association. The SH3PXD2B gene encodes a TKS4 podosome adaptor protein that regulates the epidermal growth factor signaling pathway. This study validates the critical function of the TKS4 podosome protein by suggesting a common mechanism underlying the pathogenesis of FTHS.
Topics: Adaptor Proteins, Signal Transducing; Craniofacial Abnormalities; Developmental Disabilities; Heart Defects, Congenital; Humans; Infant, Newborn; Male; Mutation; Osteochondrodysplasias; Podosomes
PubMed: 35205281
DOI: 10.3390/genes13020236 -
Trends in Cell Biology Feb 2019Matrix proteolysis mediated by MT1-MMP facilitates the invasive migration of tumor cells in dense tissues, which otherwise get trapped in the matrix because of limited... (Review)
Review
Matrix proteolysis mediated by MT1-MMP facilitates the invasive migration of tumor cells in dense tissues, which otherwise get trapped in the matrix because of limited nuclear deformability. A digest-on-demand response has been identified, which requires nucleus-microtubule linkage through the LINC complex and triggers MT1-MMP surface-exposure to facilitate nucleus movement.
Topics: Cell Movement; Cell Nucleus; Extracellular Matrix; Humans; Lamin Type A; Matrix Metalloproteinase 14; Microtubules; Models, Biological; Neoplasm Invasiveness; Neoplasms; Podosomes
PubMed: 30573318
DOI: 10.1016/j.tcb.2018.11.006 -
Experimental & Molecular Medicine Mar 2022Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate...
Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate (IS), are poorly removed during hemodialysis, leading to vascular endothelial dysfunction and leukocyte extravasation. These processes can be related to dynamic adhesion structures called podosomes. Several studies have indicated the role of integrin-linked kinase (ILK) in the accumulation of integrin-associated proteins in podosomes. Here, we investigated the involvement of ILK and podosome formation in the adhesion and extravasation of monocytes under p-cresol (pc) and IS exposure. Incubation of THP-1 human monocyte cells with these toxins upregulated ILK kinase activity. Together, both toxins increased cell adhesion, podosome formation, extracellular matrix degradation, and migration of THP-1 cells, whereas ILK depletion with specific small interfering RNAs suppressed these processes. Interestingly, F-actin colocalized with cortactin in podosome cores, while ILK was colocalized in podosome rings under toxin stimulation. Podosome Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP) and AKT protein depletion demonstrated that monocyte adhesion depends on podosome formation and that the ILK/AKT signaling pathway is involved in these processes. Ex vivo experiments showed that both toxins induced adhesion and podosome formation in leukocytes from wild-type mice, whereas these effects were not observed in leukocytes of conditional ILK-knockdown animals. In summary, under pc and IS stimulation, monocytes increase podosome formation and transmigratory capacity through an ILK/AKT signaling pathway-dependent mechanism, which could lead to vascular injury. Therefore, ILK could be a potential therapeutic target for the treatment of vascular damage associated with CKD.
Topics: Animals; Cell Adhesion; Cresols; Cytoskeletal Proteins; Humans; Indican; Mice; Monocytes; Podosomes; Protein Serine-Threonine Kinases; THP-1 Cells
PubMed: 35246616
DOI: 10.1038/s12276-022-00738-8 -
Journal of Cell Science Dec 2014The kinesin KIF1C is known to regulate podosomes, actin-rich adhesion structures that remodel the extracellular matrix during physiological processes. Here, we show that...
The kinesin KIF1C is known to regulate podosomes, actin-rich adhesion structures that remodel the extracellular matrix during physiological processes. Here, we show that KIF1C is a player in the podosome-inducing signaling cascade. Upon induction of podosome formation by protein kinase C (PKC), KIF1C translocation to the cell periphery intensifies and KIF1C accumulates both in the proximity of peripheral microtubules that show enrichment for the plus-tip-associated proteins CLASPs and around podosomes. Importantly, without CLASPs, both KIF1C trafficking and podosome formation are suppressed. Moreover, chimeric mitochondrially targeted CLASP2 recruits KIF1C, suggesting a transient CLASP-KIF1C association. We propose that CLASPs create preferred microtubule tracks for KIF1C to promote podosome induction downstream of PKC.
Topics: Animals; Cell Line; Cell Surface Extensions; Humans; Kinesins; Microtubule-Associated Proteins; Microtubules; Models, Biological; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein Kinase C; Protein Transport; Rats; Signal Transduction
PubMed: 25344256
DOI: 10.1242/jcs.149633 -
PloS One 2011Podosomes, important structures for adhesion and extracellular matrix degradation, are claimed to be involved in cell migration. In addition, podosomes are also reported...
Podosomes, important structures for adhesion and extracellular matrix degradation, are claimed to be involved in cell migration. In addition, podosomes are also reported to be of importance in tissue remodelling, e.g., in osteoclast-mediated bone resorption. Podosomes are highly dynamic actin-filament scaffolds onto which proteins important for their function, such as matrix metallo-proteases and integrins, attach. The dynamics of the podosomes require the action of many proteins regulating actin assembly and disassembly. One such protein, gelsolin, which associates to podosomes, has been reported to be important for podosome formation and function in osteoclasts. However, podosome-like structures have been reported in gelsolin-deficient dendritic cells, but the identity of these structures was not confirmed, and their dynamics and function was not investigated. Like many other cells, dendritic cells of the immune system also form matrix degrading podosomes. In the present study, we show that dendritic cells form podosomes independently of gelsolin, that there are no major alterations in their dynamics of formation and disassembly, and that they exhibit matrix-degrading function. Furthermore, we found that gelsolin is not required for TLR4-induced podosome disassembly. Thus, the actin cytoskeleton of podosomes involved in dendritic cell extracellular matrix degradation appears to be regulated differently than the cytoskeleton in podosomes of osteoclasts mediating bone resorption.
Topics: Actins; Animals; Blotting, Western; Cells, Cultured; Cytoskeleton; Dendritic Cells; Extracellular Matrix; Female; Gelsolin; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout
PubMed: 21779330
DOI: 10.1371/journal.pone.0021615 -
Cytoskeleton (Hoboken, N.J.) Dec 2011Tks5 is a Src substrate and adaptor protein previously recognized for its regulation of cancer cell invasion through modulation of specialized adhesion structures called...
Tks5 is a Src substrate and adaptor protein previously recognized for its regulation of cancer cell invasion through modulation of specialized adhesion structures called podosomes/invadopodia. Here we show for the first time that Tks5 localizes to the podosomes of primary macrophages, and that Tks5 protein levels increase concurrently with podosome deposition during the differentiation of monocytes into macrophages. Similar results are reported for model THP-1 cells, which differentiate into macrophages and form proteolytically active podosomes in response to a PKC signaling agonist (PMA) and with sensitivity to a PKC inhibitor (bisindolylmaleimide). Genetic manipulation of Tks5 expression (silencing and overexpression) in stable THP-1 cell lines does not independently alter this macrophage differentiation process. Nor do these cells lose the ability to focalize F-actin and its accessory proteins into podosome-like structures following PMA treatment. However, Tks5 directly controls podosome-associated gelatin degradation and invasion through collective changes in adhesion, chemotaxis, and the expression/proteolytic activity of MMP9. The Src family kinase-dependent phosphorylation of Tks5 is also implicated in the regulation of THP-1 macrophage invasive behavior. These results therefore define a previously unappreciated function of Tks5 signaling specific to the functional attributes of the macrophage podosome in adhesion, motility, and extracellular matrix-remodeling.
Topics: Adaptor Proteins, Vesicular Transport; Biomarkers; Cell Line, Tumor; Cell Movement; Humans; Macrophages; Phosphoproteins; Signal Transduction
PubMed: 22021214
DOI: 10.1002/cm.20545