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European Journal of Cell Biology Apr 2022Cytoskeletal elements are the key players in cellular integrity, structure, signalling and migration. Each cytoskeletal element comprises of properties with respect to... (Review)
Review
Cytoskeletal elements are the key players in cellular integrity, structure, signalling and migration. Each cytoskeletal element comprises of properties with respect to its structure and stability, which serve a specific array of functions. These structures are highly dynamic and regulated by modulation via direct interaction or post-translational modifications. HDAC6 is a cytoplasmic deacetylase known to regulate a wide range of cellular functions either through its deacetylase activity or direct interaction via its C-terminal ZnF UBP domain. HDAC6 has been widely studied for its role in aggresome formation, which acts as a protective mechanism upon protein aggregation. HDAC6 is known to play a critical role in the regulation of cytoskeletal elements-microtubules and actin filaments. This review summarizes the regulatory role of HDAC6 in cytoskeletal remodeling and dynamics of neuronal cells and its significance in neurodegenerative diseases.
Topics: Histone Deacetylase 6; Humans; Microtubules; Neurodegenerative Diseases; Neurons; Protein Aggregates; Protein Processing, Post-Translational
PubMed: 35092942
DOI: 10.1016/j.ejcb.2022.151202 -
Matrix Biology : Journal of the... Jan 2017Degradation of the extracellular matrix is a critical step of tumor cell invasion. Both protease-dependent and -independent mechanisms have been described as alternate... (Review)
Review
Degradation of the extracellular matrix is a critical step of tumor cell invasion. Both protease-dependent and -independent mechanisms have been described as alternate processes in cancer cell motility. Interestingly, some effectors of protease-dependent degradation are focalized at invadosomes and are directly coupled with contractile and adhesive machineries composed of multiple mechanosensitive proteins. This review presents recent findings in protease-dependent mechanisms elucidating the ways the force affects extracellular matrix degradation by targeting protease expression and activity at invadosome. The aim is to highlight mechanosensing and mechanotransduction processes to direct the degradative activity at invadosomes, with the focus on membrane tension, proteases and mechanosensitive ion channels.
Topics: Biomechanical Phenomena; Calcium Channels; Cell Adhesion; Cell Membrane; Cell Movement; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinases; Mechanotransduction, Cellular; Neoplasm Proteins; Neoplasms; Podosomes; Sodium Channels; Surface Tension
PubMed: 27392543
DOI: 10.1016/j.matbio.2016.06.007 -
The Journal of Cell Biology Mar 2024The microtubule-associated protein MAP1B has been implicated in axonal growth and brain development. We found that MAP1B is highly expressed in the most aggressive and...
The microtubule-associated protein MAP1B has been implicated in axonal growth and brain development. We found that MAP1B is highly expressed in the most aggressive and deadliest breast cancer subtype, triple-negative breast cancer (TNBC), but not in other subtypes. Expression of MAP1B was found to be highly correlated with poor prognosis. Depletion of MAP1B in TNBC cells impairs cell migration and invasion concomitant with a defect in tumorigenesis. We found that MAP1B interacts with key components for invadopodia formation, cortactin, and Tks5, the latter of which is a PtdIns(3,4)P2-binding and scaffold protein that localizes to invadopodia. We also found that Tks5 associates with microtubules and supports the association between MAP1B and α-tubulin. In accordance with their interaction, depletion of MAP1B leads to Tks5 destabilization, leading to its degradation via the autophagic pathway. Collectively, these findings suggest that MAP1B is a convergence point of the cytoskeleton to promote malignancy in TNBC and thereby a potential diagnostic and therapeutic target for TNBC.
Topics: Humans; Carcinogenesis; Cell Transformation, Neoplastic; Cortactin; Microtubule-Associated Proteins; Triple Negative Breast Neoplasms; MDA-MB-231 Cells; Adaptor Proteins, Vesicular Transport; Microtubules; Cytoskeleton; Female; Animals; Mice; Mice, Inbred BALB C; Podosomes; Tubulin
PubMed: 38353696
DOI: 10.1083/jcb.202303102 -
Scientific Reports Jan 2018Podosomes are dynamic actin-based membrane protrusions that are important for extracellular matrix degradation and invasive cell motility. Individual podosomes are often...
Podosomes are dynamic actin-based membrane protrusions that are important for extracellular matrix degradation and invasive cell motility. Individual podosomes are often found to organize into large rosette-like structures in some types of cells, such as osteoclasts, endothelial cells, Src-transformed fibroblasts, and certain highly invasive cancer cells. In this study, we show that new podosome rosettes arise through one of two mechanisms; de novo assembly or fission of a pre-existing podosome rosette in Src-transformed fibroblasts. Fission is a more efficient way than de novo assembly to generate new podosome rosettes in these cells. Podosome rosettes undergoing fission possess higher motility and a stronger matrix-degrading capability. Podosome rosette fission may be the result of polarized myosin II-mediated contractility of these structures, which is coordinately regulated by myosin light chain kinase and Rho-associated kinase II. Collectively, this study unveils a previously unknown mechanism-fission for the biogenesis of podosome rosettes.
Topics: Actins; Amides; Animals; Azepines; Cell Line, Tumor; Cell Membrane; Cell Movement; Humans; Mice; Microscopy, Fluorescence; Mutagenesis, Site-Directed; Myosin-Light-Chain Kinase; NIH 3T3 Cells; Naphthalenes; Podosomes; Pyridines; RNA Interference; RNA, Small Interfering; Rosette Formation; rho-Associated Kinases; src-Family Kinases
PubMed: 29323185
DOI: 10.1038/s41598-017-18861-2 -
Small GTPases Sep 2018Metastatization is a complex multistep process requiring fine-tuned regulated cytoskeleton re-modeling, mediated by the cross-talk of actin with interacting partners,... (Review)
Review
Metastatization is a complex multistep process requiring fine-tuned regulated cytoskeleton re-modeling, mediated by the cross-talk of actin with interacting partners, such as the Rho GTPases. Our expanding knowledge of invadopodia, small invasive membrane protrusions composed of a core of F-actin, actin regulators and actin-binding proteins, and hotspots for secretion of extracellular matrix (ECM) proteinases, contributes to clarify critical steps of the metastatic program. Growth factor receptors and their intermediate signaling molecules, along with matrix adhesion and rigidity, pH and hypoxia, act as drivers of cytoskeleton changes and invadopodia formation. We recently pro-posed a novel route map by which cancer cells regulates invadopodia dynamics supporting metastasis as response to the endothelin A receptor (ETR), among the highly druggable G-protein coupled receptors in cancer. The metastatic behavior exhibited by ovarian cancer cells overe-xpressing ETR is now explained by the interplay with β-arrestin1 (β-arr1), a scaffold protein acting as signal-integrating module of RhoC and cofilin signaling for specific invadopodia formation, accomplished by its interaction with a Rho guanine nucleotide exchange factor (GEF), PDZ-RhoGEF, in a G-protein independent manner. Here, we summarize this novel activation of the RhoC pathway from ETR/β-arr1 signaling that may be exploited therapeutically and discuss new perspectives for future directions of investigations.
Topics: Humans; Podosomes; Receptor, Endothelin A; beta-Arrestin 1
PubMed: 27690729
DOI: 10.1080/21541248.2016.1235526 -
Cell Reports Aug 2023Invadopodia are extracellular matrix (ECM) degrading structures, which promote cancer cell invasion. The nucleus is increasingly viewed as a mechanosensory organelle...
Invadopodia are extracellular matrix (ECM) degrading structures, which promote cancer cell invasion. The nucleus is increasingly viewed as a mechanosensory organelle that determines migratory strategies. However, how the nucleus crosstalks with invadopodia is little known. Here, we report that the oncogenic septin 9 isoform 1 (SEPT9_i1) is a component of breast cancer invadopodia. SEPT9_i1 depletion diminishes invadopodium formation and the clustering of the invadopodium precursor components TKS5 and cortactin. This phenotype is characterized by deformed nuclei and nuclear envelopes with folds and grooves. We show that SEPT9_i1 localizes to the nuclear envelope and juxtanuclear invadopodia. Moreover, exogenous lamin A rescues nuclear morphology and juxtanuclear TKS5 clusters. Importantly, SEPT9_i1 is required for the amplification of juxtanuclear invadopodia, which is induced by the epidermal growth factor. We posit that nuclei of low deformability favor the formation of juxtanuclear invadopodia in a SEPT9_i1-dependent manner, which functions as a tunable mechanism for overcoming ECM impenetrability.
Topics: Humans; Female; Septins; Podosomes; Protein Isoforms; Breast Neoplasms; Adaptor Proteins, Vesicular Transport; Cell Line, Tumor; Neoplasm Invasiveness
PubMed: 37516960
DOI: 10.1016/j.celrep.2023.112893 -
Costameres, dense plaques and podosomes: the cell matrix adhesions in cardiovascular mechanosensing.Journal of Muscle Research and Cell... Jun 2019The stiffness of the cardiovascular environment changes during ageing and in disease and contributes to disease incidence and progression. For instance, increased... (Review)
Review
The stiffness of the cardiovascular environment changes during ageing and in disease and contributes to disease incidence and progression. For instance, increased arterial stiffness can lead to atherosclerosis, while stiffening of the heart due to fibrosis can increase the chances of heart failure. Cells can sense the stiffness of the extracellular matrix through integrin adhesions and other mechanosensitive structures and in response to this initiate mechanosignalling pathways that ultimately change the cellular behaviour. Over the past decades, interest in mechanobiology has steadily increased and with this also our understanding of the molecular basis of mechanosensing and transduction. However, much of our knowledge about the mechanisms is derived from studies investigating focal adhesions in non-muscle cells, which are distinct in several regards from the cell-matrix adhesions in cardiomyocytes (costameres) or vascular smooth muscle cells (dense plaques or podosomes). Therefore, we will look here first at the evidence for mechanical sensing in the cardiovascular system, before comparing the different cytoskeletal arrangements and adhesion sites in cardiomyocytes and vascular smooth muscle cells and what is known about mechanical sensing through the various structures.
Topics: Animals; Cell Adhesion; Extracellular Matrix; Fibrosis; Heart Diseases; Humans; Integrins; Mechanotransduction, Cellular; Muscle, Smooth, Vascular; Myocytes, Cardiac; Myocytes, Smooth Muscle; Podosomes
PubMed: 31214894
DOI: 10.1007/s10974-019-09529-7 -
Trends in Cell Biology Jul 2016Atherosclerosis, cancer, and various chronic fibrotic conditions are characterized by an increase in the migratory behavior of resident cells and the enhanced invasion... (Review)
Review
Atherosclerosis, cancer, and various chronic fibrotic conditions are characterized by an increase in the migratory behavior of resident cells and the enhanced invasion of assorted exogenous cells across a stiffened extracellular matrix (ECM). This stiffened scaffold aberrantly engages cellular mechanosignaling networks in cells, which promotes the assembly of invadosomes and lamellae for cell invasion and migration. Accordingly, deciphering the conserved molecular mechanisms whereby matrix stiffness fosters invadosome and lamella formation could identify therapeutic targets to treat fibrotic conditions, and reducing ECM stiffness could ameliorate disease progression.
Topics: Animals; Biomechanical Phenomena; Cell Movement; Disease; Extracellular Matrix; Humans; Neoplasm Invasiveness; Podosomes
PubMed: 27056543
DOI: 10.1016/j.tcb.2016.03.007 -
Biophysical Journal Mar 2018Invadopodia are membrane protrusions dynamically assembled by invasive cancer cells in contact with the extracellular matrix (ECM). Invadopodia are enriched by the...
Invadopodia are membrane protrusions dynamically assembled by invasive cancer cells in contact with the extracellular matrix (ECM). Invadopodia are enriched by the structural proteins actin and cortactin as well as metalloproteases such as MT1-MMP, whose function is to degrade the surrounding ECM. During metastasis, invadopodia are necessary for cancer cell intravasation and extravasation. Although signaling pathways involved in the assembly and function of invadopodia are well studied, few studies address invadopodia dynamics and how the cell-ECM interactions contribute to cell invasion. Using iterative analysis based on time-lapse microscopy and mathematical modeling of invasive cancer cells, we found that cells oscillate between invadopodia presence and cell stasis-termed the "invadopodia state"-and invadopodia absence during cell translocation-termed the "migration state." Our data suggest that β1-integrin-ECM binding and ECM cross-linking control the duration of each of the two states. By changing the concentration of cross-linkers in two-dimensional and three-dimensional cultures, we generate an ECM in which 0-0.92 of total lysine residues are cross-linked. Using an ECM with a range of cross-linking degrees, we demonstrate that the dynamics of invadopodia-related functions have a biphasic relationship to ECM cross-linking. At intermediate levels of ECM cross-linking (0.39), cells exhibit rapid invadopodia protrusion-retraction cycles and rapid calcium spikes, which lead to more frequent MT1-MMP delivery, causing maximal invadopodia-mediated ECM degradation. In contrast, both extremely high or low levels of cross-linking lead to slower invadopodia-related dynamics and lower ECM degradation. Additionally, β1-integrin inhibition modifies the dynamics of invadopodia-related functions as well as the length of time cells spend in either of the states. Collectively, these data suggest that β1-integrin-ECM binding nonlinearly translates small physical differences in the extracellular environment to differences in the dynamics of cancer cell behaviors. Understanding the conditions under which invadopodia can be reduced by subtle environment-targeting treatments may lead to combination therapies for preventing metastatic spread.
Topics: Animals; Calcium; Cell Line, Tumor; Cell Membrane; Cell Movement; Extracellular Matrix; Integrin beta1; Mice; Molecular Imaging; Neoplasm Metastasis; Podosomes
PubMed: 29590602
DOI: 10.1016/j.bpj.2018.01.027 -
Nature Communications Nov 2019Basement membrane transmigration during embryonal development, tissue homeostasis and tumor invasion relies on invadosomes, a collective term for invadopodia and...
Basement membrane transmigration during embryonal development, tissue homeostasis and tumor invasion relies on invadosomes, a collective term for invadopodia and podosomes. An adequate structural framework for this process is still missing. Here, we reveal the modular actin nano-architecture that enables podosome protrusion and mechanosensing. The podosome protrusive core contains a central branched actin module encased by a linear actin module, each harboring specific actin interactors and actin isoforms. From the core, two actin modules radiate: ventral filaments bound by vinculin and connected to the plasma membrane and dorsal interpodosomal filaments crosslinked by myosin IIA. On stiff substrates, the actin modules mediate long-range substrate exploration, associated with degradative behavior. On compliant substrates, the vinculin-bound ventral actin filaments shorten, resulting in short-range connectivity and a focally protrusive, non-degradative state. Our findings redefine podosome nanoscale architecture and reveal a paradigm for how actin modularity drives invadosome mechanosensing in cells that breach tissue boundaries.
Topics: Actins; Animals; Cell Adhesion; Cell Membrane; Cell Movement; Cells, Cultured; Dendritic Cells; Humans; Mechanotransduction, Cellular; Mice; Podosomes
PubMed: 31729386
DOI: 10.1038/s41467-019-13123-3