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Steroids May 2018Paxillin is a group III LIM domain protein that is best characterized as a cytoplasmic scaffold/adaptor protein that functions primarily as a mediator of focal adhesion.... (Review)
Review
Paxillin is a group III LIM domain protein that is best characterized as a cytoplasmic scaffold/adaptor protein that functions primarily as a mediator of focal adhesion. However, emerging studies indicate that paxillin's functions are far broader. Not only does paxillin appear to regulate cytoplasmic kinase signaling, but it also cycles between the cytoplasm and nucleus, and may serve as an important regulator of mRNA trafficking and subsequent translation. Herein, we provide some insights suggesting that paxillin, like its relative Hic-5, has nuclear binding partners and mediates critical processes within the nucleus, at least in part functioning as coregulator of nuclear receptors and nuclear kinases to mediate genomic signaling.
Topics: Amino Acid Motifs; Animals; Cell Nucleus; Humans; Molecular Targeted Therapy; Nuclear Export Signals; Paxillin
PubMed: 29097144
DOI: 10.1016/j.steroids.2017.10.012 -
American Journal of Physiology.... Mar 2020PAK4 is the only member of the Group II p21-activated kinases (PAKs) present in rat pancreatic acinar cells and is activated by gastrointestinal...
PAK4 is the only member of the Group II p21-activated kinases (PAKs) present in rat pancreatic acinar cells and is activated by gastrointestinal hormones/neurotransmitters stimulating PLC/cAMP and by various pancreatic growth factors. However, little is known of the role of PAK4 activation in cellular signaling cascades in pancreatic acinar cells. In the present study, we examined the role of PAK4's participation in five different cholecystokinin-8 (CCK-8)-stimulated signaling pathways (PI3K/Akt, MAPK, focal adhesion kinase, GSK3, and β-catenin), which mediate many of its physiological acinar-cell effects, as well as effects in pathophysiological conditions. To define PAK4's role, the effect of two different PAK4 inhibitors, PF-3758309 and LCH-7749944, was examined under experimental conditions that only inhibited PAK4 activation and not activation of the other pancreatic PAK, Group I PAK2. The inhibitors' effects on activation of these five signaling cascades by both physiological and pathophysiological concentrations of CCK, as well as by 12--tetradecanoylphobol-13-acetate (TPA), a PKC-activator, were examined. CCK/TPA activation of focal adhesion kinases(PYK2/p125) and the accompanying adapter proteins (paxillin/p130), Mek1/2, and p44/42, but not c-Raf or other MAPKs (JNK/p38), were mediated by PAK4. Activation of PI3K/Akt/p70s6K was independent of PAK4, whereas GSK3 and β-catenin stimulation was PAK4-dependent. These results, coupled with recent studies showing PAK4 is important in pancreatic fluid/electrolyte/enzyme secretion and acinar cell growth, show that PAK4 plays an important role in different cellular signaling cascades, which have been shown to mediate numerous physiological and pathophysiological processes in pancreatic acinar cells. In pancreatic acinar cells, cholecystokinin (CCK) or 12--tetradecanoylphobol-13-acetate (TPA) activation of focal adhesion kinases (p125,PYK2) and its accompanying adapter proteins, p130CAS/paxillin; Mek1/2, p44/42, GSK3, and β-catenin are mediated by PAK4. PI3K/Akt/p70s6K, c-Raf, JNK, or p38 pathways are independent of PAK4 activation.
Topics: Acinar Cells; Animals; Crk-Associated Substrate Protein; Enzyme Activation; Enzyme Activators; Extracellular Signal-Regulated MAP Kinases; Focal Adhesion Kinase 1; Focal Adhesion Kinase 2; Glycogen Synthase Kinase 3; Male; Mitogen-Activated Protein Kinase Kinases; Pancreas, Exocrine; Paxillin; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Signal Transduction; beta Catenin; p21-Activated Kinases
PubMed: 31984786
DOI: 10.1152/ajpgi.00229.2019 -
European Review For Medical and... Apr 2017Identifying and studying the molecular mechanisms of neovascularization biomarkers are critical for conquering many diseases, such as corneal diseases and cancer.... (Review)
Review
Identifying and studying the molecular mechanisms of neovascularization biomarkers are critical for conquering many diseases, such as corneal diseases and cancer. Paxillin is an important cell scaffold and cellular signaling protein, especially a key molecule of the Integrin-mediated downstream signaling transduction. This review summarizes the structure and functions of paxillin, and the research progress of its roles in neovascularization. Although there are still some problems to be solved, paxillin may become an important target of anti-neovascularization therapies.
Topics: Humans; Neovascularization, Pathologic; Paxillin; Signal Transduction
PubMed: 28485804
DOI: No ID Found -
EMBO Reports Nov 2023The remodeling and stiffening of the extracellular matrix (ECM) is a well-recognized modulator of breast cancer progression. How changes in the mechanical properties of...
The remodeling and stiffening of the extracellular matrix (ECM) is a well-recognized modulator of breast cancer progression. How changes in the mechanical properties of the ECM are converted into biochemical signals that direct tumor cell migration and metastasis remain poorly characterized. Here, we describe a new role for the autophagy-inducing serine/threonine kinases ULK1 and ULK2 in mechanotransduction. We show that ULK1/2 activity inhibits the assembly of actin stress fibers and focal adhesions (FAs) and as a consequence impedes cell contraction and migration, independent of its role in autophagy. Mechanistically, we identify PXN/paxillin, a key component of the mechanotransducing machinery, as a direct binding partner and substrate of ULK1/2. ULK-mediated phosphorylation of PXN at S32 and S119 weakens homotypic interactions and liquid-liquid phase separation of PXN, impairing FA assembly, which in turn alters the mechanical properties of breast cancer cells and their response to mechanical stimuli. ULK1/2 and the well-characterized PXN regulator, FAK/Src, have opposing functions on mechanotransduction and compete for phosphorylation of adjacent serine and tyrosine residues. Taken together, our study reveals ULK1/2 as important regulator of PXN-dependent mechanotransduction.
Topics: Humans; Female; Paxillin; Breast Neoplasms; Mechanotransduction, Cellular; Phosphorylation; Cell Movement; Serine; Autophagy-Related Protein-1 Homolog; Intracellular Signaling Peptides and Proteins
PubMed: 37846507
DOI: 10.15252/embr.202356850 -
Biochimica Et Biophysica Acta. Proteins... Oct 2022Paxillin is one of the most important adapters in integrin-mediated adhesions that performs numerous crucial functions relying on its dynamic interactions. Its... (Review)
Review
Paxillin is one of the most important adapters in integrin-mediated adhesions that performs numerous crucial functions relying on its dynamic interactions. Its structural behavior serves different purposes, providing a base for several activities. The various domains of paxillin display different functions in the whole process of cell movements and have a significant role in cell adhesion, migration, signal transmission, and protein-protein interactions. On the other hand, some paxillin-associated proteins provide a unique spatiotemporal mechanism for regulating its dynamic characteristics in the tissue homeostasis and make it a more complex and decisive protein at the focal adhesions. This review briefly describes the structural adaptations and molecular mechanisms of recruitment of paxillin into adhesions, explains paxillin's binding dynamics and impact on adhesion stability and turnover, and reveals a variety of paxillin-associated regulatory mechanisms and how paxillin is embedded into the signaling networks.
Topics: Cell Adhesion; Cell Movement; Focal Adhesions; Paxillin; Signal Transduction
PubMed: 35926716
DOI: 10.1016/j.bbapap.2022.140825 -
Clinical Oral Investigations Mar 2021Integrins function to bind cells to extracellular matrix in tissues, which triggers downstream signaling cascades that are important in cell survival, proliferation,...
OBJECTIVE
Integrins function to bind cells to extracellular matrix in tissues, which triggers downstream signaling cascades that are important in cell survival, proliferation, cytokine activation, and cytoskeleton reorganization. These processes also play significant roles in neoplasms. This work aimed to investigate the pattern of expression of FAK, paxillin, and PI3K in ameloblastoma and adenomatoid odontogenic tumor (AOT).
MATERIALS AND METHODS
Immunohistochemistry was used to study FAK, paxillin, and PI3K in 45 ameloblastomas (32 conventional, 12 unicystic, and 1 peripheral types), 7 AOTs, and two developing human teeth.
RESULTS
Weak expression of FAK was seen in all AOT cases, while ameloblastoma had varying expression patterns, mostly strong to weak. The pattern of expression of paxillin and PI3K was relatively similar in both tumor types. In the dental germ, FAK and paxillin stained all the enamel organ components, while PI3K stained strongly the inner enamel epithelium. Stromal expression of FAK was not found to be useful in differentiating between tumors or tumor classes.
CONCLUSION
The expression of the proteins in the enamel organ suggests that their signaling may be important in odontogenesis. While some ameloblastomas strongly expressed FAK, all cases of AOT had weak signals suggesting low presence and phosphorylating activity of FAK in the latter.
CLINICAL RELEVANCE
A subset of FAK-positive ameloblastoma (as well as their malignant or metastasizing counterparts) which may have relatively aggressive behavior may be candidates for drug targeting of FAK as an additional management option.
Topics: Ameloblastoma; Focal Adhesion Kinase 1; Humans; Odontogenic Tumors; Paxillin; Phosphatidylinositol 3-Kinases
PubMed: 32681423
DOI: 10.1007/s00784-020-03465-4 -
Postepy Higieny I Medycyny... Oct 2016Morphology of senescent cells is constantly changing at the molecular level, which in turn leads to disruption of their function. It is connected with reduced ability to... (Review)
Review
Morphology of senescent cells is constantly changing at the molecular level, which in turn leads to disruption of their function. It is connected with reduced ability to synthesize extracellular matrix (ECM) and leads to the dysfunction of integrin adhesion molecules and adhesion clusters. In skin, these factors cause a loss of communication between the extracellular matrix and fibroblasts. This contributes to the appearance of signs of aging. The aim of this study is to draw attention to the very important molecule such as paxillin, which is an adaptor protein with mass of 68 kDa. This family of proteins includes Hic-5, PaxB and leupaxin. Paxillin binds to actin-binding proteins such as vinculin, actopaxin, and kinases (e.g. Integrin-linked kinase (ILK)). Moreover, it plays an important role in the integrity of the matrix, because it transduces transmembrane signaling between integrins and growth factors. Paxillin is a scaffold protein, activating the arrangement and organization of the cytoskeleton. Signaling through paxillin affects the long-term changes in gene expression, cell proliferation, and organization of the ECM. Correct functioning of the ECM is important for the wound healing processes and regeneration of tissues or tissue repair. Decrease or lack of paxillin expression results in changes in the structure and integrity of the ECM, which are manifested by aging of cells and organs. Restoration of the cellular matrix connections would be a significant element in the processes related to the anti-aging activities.
Topics: Aging; Animals; Cytoskeletal Proteins; Extracellular Matrix; Humans; Integrins; Intercellular Signaling Peptides and Proteins; Paxillin; Protein Binding; Signal Transduction; Skin; Skin Physiological Phenomena
PubMed: 27708212
DOI: 10.5604/17322693.1221385 -
HGF/c-Met/β1-integrin signalling axis induces tunneling nanotubes in A549 lung adenocarcinoma cells.Life Science Alliance Oct 2023Tunneling nanotubes (TNTs) are thin cytoplasmic extensions involved in long-distance intercellular communication and can transport intracellular organelles and...
Tunneling nanotubes (TNTs) are thin cytoplasmic extensions involved in long-distance intercellular communication and can transport intracellular organelles and signalling molecules. In cancer cells, TNT formation contributes to cell survival, chemoresistance, and malignancy. However, the molecular mechanisms underlying TNT formation are not well defined, especially in different cancers. TNTs are present in non-small cell lung cancer (NSCLC) patients with adenocarcinoma. In NSCLC, hepatocyte growth factor (HGF) and its receptor, c-Met, are mutationally upregulated, causing increased cancer cell growth, survival, and invasion. This study identifies c-Met, β1-integrin, and paxillin as novel components of TNTs in A549 lung adenocarcinoma cells, with paxillin localised at the protrusion site of TNTs. The HGF-induced TNTs in our study demonstrate the ability to transport lipid vesicles and mitochondria. HGF-induced TNT formation is mediated by c-Met and β1-integrin in conjunction with paxillin, followed by downstream activation of MAPK and PI3K pathways and the Arp2/3 complex. These findings demonstrate a potential novel approach to inhibit TNT formation through targeting HGF/c-Met receptor and β1-integrin signalling interactions, which has implications for multi-drug targeting in NSCLC.
Topics: Humans; Paxillin; Carcinoma, Non-Small-Cell Lung; Phosphatidylinositol 3-Kinases; Lung Neoplasms; Adenocarcinoma of Lung; Integrins; Hepatocyte Growth Factor
PubMed: 37550007
DOI: 10.26508/lsa.202301953 -
Nature Cell Biology Jul 2021The YAP/TAZ transcriptional programme is not only a well-established driver of cancer progression and metastasis but also an important stimulator of tissue regeneration....
The YAP/TAZ transcriptional programme is not only a well-established driver of cancer progression and metastasis but also an important stimulator of tissue regeneration. Here we identified Cerebral cavernous malformations 3 (CCM3) as a regulator of mechanical cue-driven YAP/TAZ signalling, controlling both tumour progression and stem cell differentiation. We demonstrate that CCM3 localizes to focal adhesion sites in cancer-associated fibroblasts, where it regulates mechanotransduction and YAP/TAZ activation. Mechanistically, CCM3 and focal adhesion kinase (FAK) mutually compete for binding to paxillin to fine-tune FAK/Src/paxillin-driven mechanotransduction and YAP/TAZ activation. In mouse models of breast cancer, specific loss of CCM3 in cancer-associated fibroblasts leads to exacerbated tissue remodelling and force transmission to the matrix, resulting in reciprocal YAP/TAZ activation in the neighbouring tumour cells and dissemination of metastasis to distant organs. Similarly, CCM3 regulates the differentiation of mesenchymal stromal/stem cells. In conclusion, CCM3 is a gatekeeper in focal adhesions that controls mechanotransduction and YAP/TAZ signalling.
Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis Regulatory Proteins; Breast Neoplasms; Cancer-Associated Fibroblasts; Cell Communication; Cell Differentiation; Cell Line, Tumor; Female; Focal Adhesion Kinase 1; Focal Adhesions; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Mechanotransduction, Cellular; Membrane Proteins; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Paxillin; Phosphorylation; Protein Binding; Proto-Oncogene Proteins; Stress, Mechanical; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins; src-Family Kinases
PubMed: 34226698
DOI: 10.1038/s41556-021-00702-0 -
Journal of Medicinal Chemistry Jan 2021We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the...
We report the synthesis and evaluation of a series of cell-permeable and N- versus O-selective sialyltransferase inhibitors. Inhibitor design entailed the functionalization of lithocholic acid at C(3) and at the cyclopentane ring side chain. Among the series, FCW34 and FCW66 were shown to inhibit MDA-MB-231 cell migration as effectively as ST3GALIII-gene knockdown did. FCW34 was shown to inhibit tumor growth, reduce angiogenesis, and delay cancer cell metastasis in animal models. Furthermore, FCW34 inhibited vessel development and suppressed angiogenic activity in transgenic zebrafish models. Our results provide clear evidence that FCW34-induced sialyltransferase inhibition reduces cancer cell metastasis by decreasing N-glycan sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFκB signaling pathways.
Topics: Animals; Animals, Genetically Modified; Breast Neoplasms; Catalysis; Cell Line, Tumor; Enzyme Inhibitors; Female; Focal Adhesion Protein-Tyrosine Kinases; Glycoproteins; Humans; Integrins; Isoenzymes; Molecular Docking Simulation; NF-kappa B; Neoplasm Metastasis; Paxillin; Phosphorylation; Sialyltransferases; Signal Transduction; Talin; Zebrafish
PubMed: 33371679
DOI: 10.1021/acs.jmedchem.0c01477