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Journal of Cell Science Oct 2019Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment,... (Review)
Review
Cell adhesion to the extracellular matrix is essential for cellular processes, such as migration and invasion. In response to cues from the microenvironment, integrin-mediated adhesions alter cellular behaviour through cytoskeletal rearrangements. The tight association of the actin cytoskeleton with adhesive structures has been extensively studied, whereas the microtubule network in this context has gathered far less attention. In recent years, however, microtubules have emerged as key regulators of cell adhesion and migration through their participation in adhesion turnover and cellular signalling. In this Review, we focus on the interactions between microtubules and integrin-mediated adhesions, in particular, focal adhesions and podosomes. Starting with the association of microtubules with these adhesive structures, we describe the classical role of microtubules in vesicular trafficking, which is involved in the turnover of cell adhesions, before discussing how microtubules can also influence the actin-focal adhesion interplay through RhoGTPase signalling, thereby orchestrating a very crucial crosstalk between the cytoskeletal networks and adhesions.
Topics: Actin Cytoskeleton; Animals; Cytoskeleton; Focal Adhesions; Humans; Microtubules; Signal Transduction
PubMed: 31597743
DOI: 10.1242/jcs.232843 -
International Journal of Molecular... Mar 2018Osteoclasts form a specialized cell-matrix adhesion structure, known as the "sealing zone", during bone resorption. The sealing zone is a dynamic actin-rich structure... (Review)
Review
Osteoclasts form a specialized cell-matrix adhesion structure, known as the "sealing zone", during bone resorption. The sealing zone is a dynamic actin-rich structure that defines the resorption area of the bone. The detailed dynamics and fine structure of the sealing zone have been elusive. Osteoclasts plated on glass do not form a sealing zone, but generate a separate supra-molecular structure called the "podosome belt". Podosomes are integrin-based adhesion complexes involved in matrix adhesion, cell migration, matrix degradation, and mechanosensing. Invadopodia, podosome-like protrusions in cancer cells, are involved in cell invasion into other tissues by promoting matrix degradation. Both podosomes and invadopodia exhibit actin pattern transitions during maturation. We previously found that Arp2/3-dependent actin flow occurs in all observed assembly patterns of podosomes in osteoclasts on glass. It is known that the actin wave in cells exhibits a similar pattern transition in its evolution. Because of significant advances in our understanding regarding the mechanism of podosomes/invadopodia formation over the last decade, we revisited the structure and function of the sealing zone in this review, highlighting the possible involvement of self-organized actin waves in the organogenesis of the sealing zone.
Topics: Actin-Related Protein 2-3 Complex; Animals; Bone Resorption; Cell Adhesion; Cell Differentiation; Cell Movement; Humans; Osteoclasts; Podosomes
PubMed: 29587415
DOI: 10.3390/ijms19040984 -
Cell Reports Oct 2023During metastasis, tumor cells invade through the basement membrane and intravasate into blood vessels and then extravasate into distant organs to establish metastases....
During metastasis, tumor cells invade through the basement membrane and intravasate into blood vessels and then extravasate into distant organs to establish metastases. Here, we report a critical role of a transmembrane serine protease fibroblast activation protein (FAP) in tumor metastasis. Expression of FAP and TWIST1, a metastasis driver, is significantly correlated in several types of human carcinomas, and FAP is required for TWIST1-induced breast cancer metastasis to the lung. Mechanistically, FAP is localized at invadopodia and required for invadopodia-mediated extracellular matrix degradation independent of its proteolytic activity. Live cell imaging shows that association of invadopodia precursors with FAP at the cell membrane promotes the stabilization and growth of invadopodia precursors into mature invadopodia. Together, our study identified FAP as a functional target of TWIST1 in driving tumor metastasis via promoting invadopodia-mediated matrix degradation and uncovered a proteolytic activity-independent role of FAP in stabilizing invadopodia precursors for maturation.
Topics: Humans; Female; Podosomes; Cell Line, Tumor; Peptide Hydrolases; Neoplasm Invasiveness; Breast Neoplasms; Membrane Proteins; Serine Endopeptidases; Fibroblasts; Extracellular Matrix; Melanoma, Cutaneous Malignant
PubMed: 37862167
DOI: 10.1016/j.celrep.2023.113302 -
European Journal of Cell Biology Nov 2016Invadosomes are actin rich protrusive structures that facilitate invasive migration in multiple cell types. Comprised of invadopodia and podosomes, these highly dynamic... (Review)
Review
Invadosomes are actin rich protrusive structures that facilitate invasive migration in multiple cell types. Comprised of invadopodia and podosomes, these highly dynamic structures adhere to and degrade the extracellular matrix, and are also thought to play a role in mechanosensing. Many extracellular signals have been implicated in invadosome stimulation, activating complex signalling cascades to drive the formation, activity and turnover of invadosomes. While the structural components of invadosomes have been well studied, the regulation of invadosome dynamics is still poorly understood. Protein kinases are essential to this regulation, affecting all stages of invadosome dynamics and allowing tight spatiotemporal control of their activity. Invadosome organisation and function have been linked to pathophysiological states such as cancer invasion and metastasis; therapeutic targeting of invadosome regulatory components is thus warranted. In this review, we discuss the involvement of kinase signalling in every stage of the invadosome life cycle and evaluate its significance.
Topics: Animals; Cell Adhesion; Extracellular Matrix; Humans; Neoplasm Invasiveness; Neoplasm Proteins; Neoplasms; Podosomes; Protein Kinases; Signal Transduction
PubMed: 27465307
DOI: 10.1016/j.ejcb.2016.07.002 -
Seminars in Cancer Biology May 2020A great hallmark of breast cancer is the absence or presence of estrogen receptors ERα and ERβ, with a dominant role in cell proliferation, differentiation and cancer... (Review)
Review
A great hallmark of breast cancer is the absence or presence of estrogen receptors ERα and ERβ, with a dominant role in cell proliferation, differentiation and cancer progression. Both receptors are related with Epithelial-to-Mesenchymal Transition (EMT) since there is a relation between ERs and extracellular matrix (ECM) macromolecules expression, and therefore, cell-cell and cell-ECM interactions. The endocrine resistance of ERα endows epithelial cells with increased aggressiveness and induces cell proliferation, resulting into a mesenchymal phenotype and an EMT status. ERα signaling may affect the transcriptional factors which govern EMT. Knockdown or silencing of ERα and ERβ in MCF-7 and MDA-MB-231 breast cancer cells respectively, provoked pivotal changes in phenotype, cellular functions, mRNA and protein levels of EMT markers, and consequently the EMT status. Mesenchymal cells owe their migratory and invasive properties to invadopodia, while in epithelial cells, lamellipodia and filopodia are mostly observed. Invadopodia, are actin-rich protrusions of plasma membrane, promoting proteolytic degradation of ECM and tumor invasion. Cortactin and MMP-14 govern the formation and principal functions of invadopodia. In vitro experiments proved that lumican inhibits cortactin and MMP-14 expression, alters the formation of lamellipodia and transforms mesenchymal cells into epithelial-like. Conclusively, lumican may inhibit or even reverse the several metastatic features that EMT endows in breast cancer cells. Therefore, a lumican-based anti-cancer therapy which will pharmacologically target and inhibit EMT might be interesting to be developed.
Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Epithelial-Mesenchymal Transition; Extracellular Matrix; Female; Gene Expression Regulation, Neoplastic; Humans; Lumican; Molecular Targeted Therapy; Podosomes; Signal Transduction
PubMed: 31401293
DOI: 10.1016/j.semcancer.2019.08.003 -
Critical Reviews in Oncology/hematology Mar 2021Dissemination of cancer cells is an intricate multistep process that represents the most deadly aspect of cancer. Cancer cells form F-actin-rich protrusions known as... (Review)
Review
Dissemination of cancer cells is an intricate multistep process that represents the most deadly aspect of cancer. Cancer cells form F-actin-rich protrusions known as invadopodia to invade surrounding tissues, blood vessels and lymphatics. A number of studies have demonstrated the significant roles of invadopodia in cancer. Therefore, the specific cells and molecules involved in invadopodia activity can provide as therapeutic targets. In this review, we included a thorough overview of studies in invadopodia and discussed their functions in cancer metastasis. We then presented the specific cells and molecules involved in invadopodia activity in pancreatic cancer and analyzed their suitability to be effective therapeutic targets. Currently, drugs targeting invadopodia and relevant clinical trials are negligible. Here, we highlighted the significance of potential drugs and discussed future obstacles in implementing clinical trials. This review presents a new perspective on invadopodia-induced pancreatic cancer metastasis and may prosper the development of targeted therapeutics against pancreatic cancer.
Topics: Cell Line, Tumor; Extracellular Matrix; Humans; Neoplasm Invasiveness; Pancreatic Neoplasms; Podosomes
PubMed: 33482351
DOI: 10.1016/j.critrevonc.2021.103236 -
Journal of Cellular and Molecular... Mar 2020In the ageing skeleton, the balance of bone reconstruction could commonly be broken by the increasing of bone resorption and decreasing of bone formation. Consequently,... (Review)
Review
In the ageing skeleton, the balance of bone reconstruction could commonly be broken by the increasing of bone resorption and decreasing of bone formation. Consequently, the bone resorption gradually occupies a dominant status. During this imbalance process, osteoclast is unique cell linage act the bone resorptive biological activity, which is a highly differentiated ultimate cell derived from monocyte/macrophage. The erosive function of osteoclasts is that they have to adhere the bone matrix and migrate along it, in which adhesive cytoskeleton recombination of osteoclast is essential. In that, the podosome is a membrane binding microdomain organelle, based on dynamic actin, which forms a cytoskeleton superstructure connected with the plasma membrane. Otherwise, as the main adhesive protein, integrin regulates the formation of podosome and cytoskeleton, which collaborates with the various molecules including: c-Cbl, p130 , c-Src and Pyk2, through several signalling cascades cross talking, including: M-CSF and RANKL. In our current study, we discuss the role of integrin and associated molecules in osteoclastogenesis cytoskeletal, especially podosomes, regulation and relevant signalling cascades cross talking.
Topics: Animals; Bone Resorption; Cytoskeleton; Humans; Integrins; Macrophage Colony-Stimulating Factor; Mice; Osteoclasts; Osteogenesis; Phosphatidylinositol 3-Kinases; Podosomes; RANK Ligand; Signal Transduction; Syk Kinase
PubMed: 32045092
DOI: 10.1111/jcmm.15052 -
Cell Death and Differentiation Sep 2018Reorganization of the podosome into the sealing zone is crucial for osteoclasts (OCLs) to resorb bone, but the underlying mechanisms are unclear. Here, we show that...
Reorganization of the podosome into the sealing zone is crucial for osteoclasts (OCLs) to resorb bone, but the underlying mechanisms are unclear. Here, we show that tuberous sclerosis complex 1 (TSC1) functions centrally in OCLs to promote podosome organization and bone resorption through mechanistic target of rapamycin complex 1 (mTORC1) and the small GTPases Rac1/Cdc42. During osteoclastogenesis, enhanced expression of TSC1 downregulates mTORC1 activity. TSC1 deletion in OCLs reduced podosome belt formation in vitro and sealing zone formation in vivo, leading to bone resorption deficiency and osteopetrosis. Mechanistically, TSC1 promoted podosome superstructure assembly by releasing mTORC1-dependent negative feedback inhibition of Rac1/Cdc42. Rapamycin and active Rac1/Cdc42 restore podosome organization and bone resorption and alleviate osteopetrotic phenotypes in mutant mice. Our findings reveal an essential role of TSC1 signaling in the regulation of bone resorption. Targeting TSC1 represents a novel strategy to inhibit bone resorption and prevent bone loss-related diseases.
Topics: Animals; Bone Resorption; Cell Differentiation; Down-Regulation; Female; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptides; Osteoclasts; Osteogenesis; Podosomes; RAW 264.7 Cells; Signal Transduction; Sirolimus; Tuberous Sclerosis Complex 1 Protein; cdc42 GTP-Binding Protein; rac1 GTP-Binding Protein
PubMed: 29358671
DOI: 10.1038/s41418-017-0049-4 -
Journal of Virology Apr 2021Macrophages are one of the major targets of (HIV-1) and play crucial roles in viral dissemination and persistence during AIDS progression. Here, we reveal the dynamic...
Macrophages are one of the major targets of (HIV-1) and play crucial roles in viral dissemination and persistence during AIDS progression. Here, we reveal the dynamic podosome-mediated entry of HIV-1 into macrophages. Inhibition of podosomes prevented HIV-1 entry into macrophages, while stimulation of podosome formation promoted viral entry. Single-virus tracking revealed the temporal and spatial mechanism of the dynamic podosome-mediated viral entry process. The core and ring structures of podosomes played complex roles in viral entry. The HIV coreceptor, CCR5, was recruited to form specific clusters at the podosome ring, where it participated in viral entry. The podosome facilitated HIV-1 entry with a rotation mode triggered by dynamic actin. Our discovery of this novel HIV-1 entry route into macrophages, mediated by podosomes critical for cell migration and tissue infiltration, provides a new view of HIV infection and pathogenesis, which may assist in the development of new antiviral strategies.Macrophages are motile leukocytes and play critical roles in HIV-1 infection and AIDS progression. Podosomes, as small dynamic adhesion microdomains driven by the dynamic actin cytoskeleton, are mainly involved in cell migration of macrophages. Herein, we found that HIV-1 uses dynamic podosomes to facilitate its entry into macrophages. Single-virus imaging coupled with drug assays revealed the mechanism underlying the podosome-mediated route of HIV-1 entry into macrophages, including the dynamic relationship between the viral particles and the podosome core and ring structures, the CCR5 coreceptor. The dynamic podosome-mediated entry of HIV-1 into macrophages will be very significant for HIV-1 pathogenesis, especially for viral dissemination via macrophage migration and tissue infiltration. Thus, we report a novel HIV-1 entry route into macrophages mediated by podosomes, which extends our understanding of HIV infection and pathogenesis.
PubMed: 33627394
DOI: 10.1128/JVI.02480-20 -
Cellular and Molecular Life Sciences :... Oct 2018Osteoclasts are multinucleated cells responsible for bone resorption. Osteoclasts adhere to the bone surface through integrins and polarize to form actin rings, which... (Review)
Review
Osteoclasts are multinucleated cells responsible for bone resorption. Osteoclasts adhere to the bone surface through integrins and polarize to form actin rings, which are formed by the assembly of podosomes. The area contained within actin rings (also called sealing zones) has an acidic pH, which causes dissolution of bone minerals including hydroxyapatite and the degradation of matrix proteins including type I collagen by the protease cathepsin K. Osteoclasts resorb bone matrices while moving on bone surfaces. Osteoclasts change their cell shapes and exhibit three modes for bone resorption: motile resorbing mode for digging trenches, static resorbing mode for digging pits, and motile non-resorbing mode. Therefore, the actin cytoskeleton is actively remodeled in osteoclasts. Recent studies have revealed that many molecules, such as Rac, Cdc42, Rho, and small GTPase regulators and effectors, are involved in actin cytoskeletal remodeling during the formation of actin rings and resorption cavities on bone slices. In this review, we introduce how these molecules and non-canonical Wnt signaling regulate the bone-resorbing activity of osteoclasts.
Topics: Animals; Bone Resorption; Cytoskeleton; Humans; Osteoclasts; Podosomes; Wnt Signaling Pathway; cdc42 GTP-Binding Protein; rac GTP-Binding Proteins; rho GTP-Binding Proteins
PubMed: 30051162
DOI: 10.1007/s00018-018-2881-1