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Advances in Gerontology = Uspekhi... 2019Gerontocosmetology is the rapid developing knowledge area that has a very large applied meaning. Herewith a lot of information about skin aging and geroprotectors for... (Review)
Review
Gerontocosmetology is the rapid developing knowledge area that has a very large applied meaning. Herewith a lot of information about skin aging and geroprotectors for skin rejuvenation hasn't a scientific background. Thus, understanding the fundamental mechanisms of skin aging becomes the actual task of molecular gerontology. Skin fibroblasts are the polyfunctional cell population that synthesize a number of biologically active substances and participate in maintaining of extracellular matrix homeostasis, skin hydratation and endocrine and immune function. In the review genetic (accumulation of nuclear and mitochondrial DNA mistakes) and epigenetic factors of skin fibroblasts aging are described. Role of AP-1, NF-κB, c-jun, CCN1, TGF-β, TNF-α, MMP-1, MMP-3, MMP-8, MMP-9 and glycation in skin fibroblasts aging are discussed. There are some data about decreasing of skin fibroblasts ability to migration and synthesis of paxillins and aquaporin-3 (AQP3) during aging. Role of hormonal regulation in skin fibroblasts aging are described. Geroprotective action of melatonin to skin fibroblasts are showed. Reviewed molecular-cellular aspects of skin fibroblasts aging can be take into consideration for scientific background of using of cosmetic products for retarding of skin aging rate.
Topics: Cells, Cultured; Epigenesis, Genetic; Fibroblasts; Humans; Skin Aging
PubMed: 32160428
DOI: No ID Found -
Memorias Do Instituto Oswaldo Cruz 2019Cardiac physiology depends on coupling and electrical and mechanical coordination through the intercalated disc. Focal adhesions offer mechanical support and signal...
BACKGROUND
Cardiac physiology depends on coupling and electrical and mechanical coordination through the intercalated disc. Focal adhesions offer mechanical support and signal transduction events during heart contraction-relaxation processes. Talin links integrins to the actin cytoskeleton and serves as a scaffold for the recruitment of other proteins, such as paxillin in focal adhesion formation and regulation. Chagasic cardiomyopathy is caused by infection by Trypanosoma cruzi and is a debilitating condition comprising extensive fibrosis, inflammation, cardiac hypertrophy and electrical alterations that culminate in heart failure.
OBJECTIVES
Since mechanotransduction coordinates heart function, we evaluated the underlying mechanism implicated in the mechanical changes, focusing especially in mechanosensitive proteins and related signalling pathways during infection of cardiac cells by T. cruzi.
METHODS
We investigated the effect of T. cruzi infection on the expression and distribution of talin/paxillin and associated proteins in mouse cardiomyocytes in vitro by western blotting, immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR).
FINDINGS
Talin and paxillin spatial distribution in T. cruzi-infected cardiomyocytes in vitro were altered associated with a downregulation of these proteins and mRNAs levels at 72 h post-infection (hpi). Additionally, we observed an increase in the activation of the focal adhesion kinase (FAK) concomitant with increase in β-1-integrin at 24 hpi. Finally, we detected a decrease in the activation of FAK at 72 hpi in T. cruzi-infected cultures.
MAIN CONCLUSION
The results suggest that these changes may contribute to the mechanotransduction disturbance evidenced in chagasic cardiomyopathy.
Topics: Animals; Blotting, Western; Chagas Cardiomyopathy; Fluorescent Antibody Technique, Indirect; Immunoblotting; Mechanotransduction, Cellular; Mice; Myocytes, Cardiac; Paxillin; Real-Time Polymerase Chain Reaction; Talin; Trypanosoma cruzi
PubMed: 31433004
DOI: 10.1590/0074-02760180593 -
Frontiers in Neuroscience 2023The adhesion systems employed by migrating cortical neurons are not well understood. Genetic deletion studies of focal adhesion kinase (FAK) and paxillin in mice...
The adhesion systems employed by migrating cortical neurons are not well understood. Genetic deletion studies of focal adhesion kinase (FAK) and paxillin in mice suggested that these classical focal adhesion molecules control the morphology and speed of cortical neuron migration, but whether β1 integrins also regulate migration morphology and speed is not known. We hypothesized that a β1 integrin adhesion complex is required for proper neuronal migration and for proper cortical development. To test this, we have specifically deleted β1 integrin from postmitotic migrating and differentiating neurons by crossing conditional β1 integrin floxed mice into the transgenic line. Similar to our prior findings with conditional paxillin deficiency, we found that both homozygous and heterozygous deletion of β1 integrin causes transient mispositioning of cortical neurons in the developing cortex when analyzed pre- and perinatally. Paxillin and β1 integrin colocalize in the migrating neurons and deletion of paxillin in the migrating neuron causes an overall reduction of the β1 integrin immunofluorescence signal and reduction in the number of activated β1 integrin puncta in the migrating neurons. These findings suggest that these molecules may form a functional complex in migrating neurons. Similarly, there was an overall reduced number of paxillin+ puncta in the β1 integrin deficient neurons, despite the normal distribution of FAK and Cx26, a connexin required for cortical migration. The double knockout of paxillin and β1 integrin produces a cortical malpositioning phenotype similar to the paxillin or β1 integrin single knockouts, as would be expected if paxillin and β1 integrin function on a common pathway. Importantly, an isolation-induced pup vocalization test showed that β1 integrin mutants produced a significantly smaller number of calls compared to their littermate controls when analyzed at postnatal day 4 (P4) and revealed a several days trend in reduced vocalization development compared to controls. The current study establishes a role for β1 integrin in cortical development and suggests that β1 integrin deficiency leads to migration and neurodevelopmental delays.
PubMed: 37250402
DOI: 10.3389/fnins.2023.1158419 -
Cell Reports Aug 2022Soft tissue environments govern neuronal morphogenesis. However, the precise molecular mechanisms underlying chemotropism-directed axonal growth cone movement in...
Soft tissue environments govern neuronal morphogenesis. However, the precise molecular mechanisms underlying chemotropism-directed axonal growth cone movement in extremely soft environments remain unclear. Here, we show that drebrin, a growth cone T-zone protein, modulates growth cone turning in response to brain-derived neurotrophic factor (BDNF) coated on a soft substrate. Structurally, axonal growth cones of rodent hippocampal neurons grown on 0.1 kPa hydrogels possess an expanded T zone in which drebrin is highly integrated with both F-actin and microtubules. Biochemically, we identify paxillin as interacting with drebrin in cells grown on 0.1 kPa hydrogels but not on glass coverslips. When grown on 0.1 kPa substrates, growth cones asymmetrically exposed to BDNF-bound stripes exhibit enhanced paxillin-drebrin interaction on the side facing the stripes, an activity that is PKA and AAK1 dependent but independent of Src kinase. Functionally, we show that BDNF-induced growth cone turning and force generation on soft substrates require drebrin phosphorylation and paxillin-drebrin association.
Topics: Actins; Brain-Derived Neurotrophic Factor; Growth Cones; Hydrogels; Neurons; Neuropeptides; Paxillin
PubMed: 35977504
DOI: 10.1016/j.celrep.2022.111188 -
Biophysical Journal Nov 2020The eukaryotic cell develops organelles to sense and respond to the mechanical properties of its surroundings. These mechanosensing organelles aggregate into... (Review)
Review
The eukaryotic cell develops organelles to sense and respond to the mechanical properties of its surroundings. These mechanosensing organelles aggregate into symmetry-breaking patterns to mediate cell motion and differentiation on substrate. The spreading of a cell plated onto a substrate is one of the simplest paradigms in which angular symmetry-breaking assemblies of mechanical sensors are seen to develop. We review evidence for the importance of the edge of the cell-extracellular matrix adhesion area in the aggregation of mechanosensors and develop a theoretical model for the clustering of mechanosensors into nascent focal adhesions on this contact ring. To study the spatial patterns arising on this topological feature, we use a one-dimensional lattice model with a nearest-neighbor interaction between individual integrin-mediated mechanosensors. We find the effective Ginzburg-Landau free energy for this model and determine the spectrum of spatial modes as the cell spreads and increases its contact area with the substrate. To test our model, we compare its predictions with measured distributions of paxillin in spreading fibroblasts.
Topics: Cell Adhesion; Cell-Matrix Junctions; Extracellular Matrix; Focal Adhesions; Integrins; Paxillin
PubMed: 33068539
DOI: 10.1016/j.bpj.2020.09.037 -
Journal of Cell Science Sep 2023Liver injury leads to fibrosis and cirrhosis. The primary mechanism underlying the fibrogenic response is the activation of hepatic stellate cells (HSCs), which are...
Liver injury leads to fibrosis and cirrhosis. The primary mechanism underlying the fibrogenic response is the activation of hepatic stellate cells (HSCs), which are 'quiescent' in normal liver but become 'activated' after injury by transdifferentiating into extracellular matrix (ECM)-secreting myofibroblasts. Given that integrins are important in HSC activation and fibrogenesis, we hypothesized that paxillin, a key downstream effector in integrin signaling, might be critical in the fibrosis pathway. Using a cell-culture-based model of HSC activation and in vivo models of liver injury, we found that paxillin is upregulated in activated HSCs and fibrotic livers. Overexpression of paxillin (both in vitro and in vivo) led to increased ECM protein expression, and depletion of paxillin in a novel conditional mouse injury model reduced fibrosis. The mechanism by which paxillin mediated this effect appeared to be through the actin cytoskeleton, which signals to the ERK pathway and induces ECM protein production. These data highlight a novel role for paxillin in HSC biology and fibrosis.
Topics: Mice; Animals; Paxillin; Actins; Hepatic Stellate Cells; Polymerization; Liver Cirrhosis; Liver; Fibrosis; Disease Models, Animal
PubMed: 37667902
DOI: 10.1242/jcs.261122 -
Molecular Biology of the Cell Feb 2022Distant organ metastasis is linked to poor prognosis during cancer progression. The expression level of the focal adhesion adapter protein paxillin varies among...
Distant organ metastasis is linked to poor prognosis during cancer progression. The expression level of the focal adhesion adapter protein paxillin varies among different human cancers, but its role in tumor progression is unclear. Herein we utilize a newly generated PyMT mammary tumor mouse model with conditional paxillin ablation in breast tumor epithelial cells, combined with in vitro three-dimensional (3D) tumor organoids invasion analysis and 2D calcium switch assays, to assess the roles for paxillin in breast tumor cell invasion. Paxillin had little effect on primary tumor initiation and growth but is critical for the formation of distant lung metastasis. In paxillin-depleted 3D tumor organoids, collective cell invasion was substantially perturbed. The 2D cell culture revealed paxillin-dependent stabilization of adherens junctions (AJ). Mechanistically, paxillin is required for AJ assembly through facilitating E-cadherin endocytosis and recycling and HDAC6-mediated microtubule acetylation. Furthermore, Rho GTPase activity analysis and rescue experiments with a RhoA activator or Rac1 inhibitor suggest paxillin is potentially regulating the E-cadherin-dependent junction integrity and contractility through control of the balance of RhoA and Rac1 activities. Together, these data highlight new roles for paxillin in the regulation of cell-cell adhesion and collective tumor cell migration to promote the formation of distance organ metastases.
Topics: Adherens Junctions; Animals; Breast; Breast Neoplasms; Cadherins; Cell Adhesion; Cell Line, Tumor; Cell Movement; Epithelial Cells; Female; Focal Adhesions; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Invasiveness; Paxillin; rho GTP-Binding Proteins
PubMed: 34851720
DOI: 10.1091/mbc.E21-09-0432 -
Scientific Reports Mar 2023In mesenchymal cell motility, several migration patterns have been observed, including directional, exploratory and stationary. Two key members of the Rho-family of...
In mesenchymal cell motility, several migration patterns have been observed, including directional, exploratory and stationary. Two key members of the Rho-family of GTPases, Rac and Rho, along with an adaptor protein called paxillin, have been particularly implicated in the formation of such migration patterns and in regulating adhesion dynamics. Together, they form a key regulatory network that involves the mutual inhibition exerted by Rac and Rho on each other and the promotion of Rac activation by phosphorylated paxillin. Although this interaction is sufficient in generating wave-pinning that underscores cellular polarization comprised of cellular front (high active Rac) and back (high active Rho), it remains unclear how they interact collectively to induce other modes of migration detected in Chinese hamster Ovary (CHO-K1) cells. We previously developed a six-variable (6V) reaction-diffusion model describing the interactions of these three proteins (in their active/phosphorylated and inactive/unphosphorylated forms) along with other auxiliary proteins, to decipher their role in generating wave-pinning. In this study, we explored, through computational modeling and image analysis, how differences in timescales within this molecular network can potentially produce the migration patterns in CHO-K1 cells and how switching between migration modes could occur. To do so, the 6V model was reduced to an excitable 4V spatiotemporal model possessing three different timescales. The model produced not only wave-pinning in the presence of diffusion, but also mixed-mode oscillations (MMOs) and relaxation oscillations (ROs). Implementing the model using the Cellular Potts Model (CPM) produced outcomes in which protrusions in the cell membrane changed Rac-Rho localization, resulting in membrane oscillations and fast directionality variations similar to those observed experimentally in CHO-K1 cells. The latter was assessed by comparing the migration patterns of experimental with CPM cells using four metrics: instantaneous cell speed, exponent of mean-square displacement ([Formula: see text]-value), directionality ratio and protrusion rate. Variations in migration patterns induced by mutating paxillin's serine 273 residue were also captured by the model and detected by a machine classifier, revealing that this mutation alters the dynamics of the system from MMOs to ROs or nonoscillatory behaviour through variation in the scaled concentration of an active form of an adhesion protein called p21-Activated Kinase 1 (PAK). These results thus suggest that MMOs and adhesion dynamics are the key mechanisms regulating CHO-K1 cell motility.
Topics: Animals; Cricetinae; Paxillin; rho GTP-Binding Proteins; CHO Cells; Reactive Oxygen Species; Cricetulus; Cell Movement; rac GTP-Binding Proteins; Cell Polarity
PubMed: 36918704
DOI: 10.1038/s41598-023-31042-8 -
Cytoskeleton (Hoboken, N.J.) May 2024Focal adhesions serve as structural and signaling hubs, facilitating bidirectional communication at the cell-extracellular matrix interface. Paxillin and the related...
Focal adhesions serve as structural and signaling hubs, facilitating bidirectional communication at the cell-extracellular matrix interface. Paxillin and the related Hic-5 (TGFβ1i1) are adaptor/scaffold proteins that recruit numerous structural and regulatory proteins to focal adhesions, where they perform both overlapping and discrete functions. In this study, paxillin and Hic-5 were expressed in U2OS osteosarcoma cells as biotin ligase (BioID2) fusion proteins and used as bait proteins for proximity-dependent biotinylation in order to directly compare their respective interactomes. The fusion proteins localized to both focal adhesions and the centrosome, resulting in biotinylation of components of each of these structures. Biotinylated proteins were purified and analyzed by mass spectrometry. The list of proximity interactors for paxillin and Hic-5 comprised numerous shared core focal adhesion proteins that likely contribute to their similar functions in cell adhesion and migration, as well as proteins unique to paxillin and Hic-5 that have been previously localized to focal adhesions, the centrosome, or the nucleus. Western blotting confirmed biotinylation and enrichment of FAK and vinculin, known interactors of Hic-5 and paxillin, as well as several potentially unique proximity interactors of Hic-5 and paxillin, including septin 7 and ponsin, respectively. Further investigation into the functional relationship between the unique interactors and Hic-5 or paxillin may yield novel insights into their distinct roles in cell migration.
PubMed: 38801098
DOI: 10.1002/cm.21878 -
Anticancer Research Mar 2017The focal adhesion kinase (FAK)/SRC phosphorylation cascade and its downstream target paxillin have been implicated in malignant transformation, tumor growth and...
BACKGROUND/AIM
The focal adhesion kinase (FAK)/SRC phosphorylation cascade and its downstream target paxillin have been implicated in malignant transformation, tumor growth and progression, together with metastasis. The present study aimed to evaluate the clinical significance of concomitant FAK/SRC and p-paxillin expression in mobile tongue squamous cell carcinoma (SCC).
MATERIALS AND METHODS
FAK, SRC and phospho-paxillin expression in 48 mobile tongue SCC tissue samples was assessed immunohistochemically and analyzed with respect to clinicopathological characteristics and patient survival.
RESULTS
Concomitant high FAK/SRC expression was significantly associated with high grade of tumor differentiation (p=0.048) and longer disease-free patient survival (log-rank test, p=0.019). High p-paxillin expression was significantly associated with greater depth of invasion (p=0.002), lymph node metastasis (p=0.048) and poorer disease-free patient survival (log-rank test, p=0.021; Cox-regression analysis, p=0.031).
CONCLUSION
The present study provides evidence that FAK/SRC and paxillin play a role in the pathophysiological aspects of mobile tongue SCC and could constitute therapeutic targets.
Topics: Aged; Carcinoma, Squamous Cell; Cell Differentiation; Disease Progression; Disease-Free Survival; Female; Focal Adhesion Protein-Tyrosine Kinases; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Middle Aged; Paxillin; Prognosis; Proportional Hazards Models; Tongue Neoplasms; Treatment Outcome; src-Family Kinases
PubMed: 28314297
DOI: 10.21873/anticanres.11449