-
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 -
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 -
International Journal of Molecular... Nov 2022Integrins allow cells to adhere to the extracellular matrix and promote the recruitment of other integrins, resulting in the formation of focal adhesion sites at the... (Review)
Review
Integrins allow cells to adhere to the extracellular matrix and promote the recruitment of other integrins, resulting in the formation of focal adhesion sites at the binding sites. Focal adhesion sites play essential roles in the assembly of the cytoskeleton and are vital in shaping the structure of cells. They also play other regulatory roles by influencing numerous biological functions, such as cell proliferation and apoptosis. Hydrogen peroxide‑inducible clone 5 (Hic‑5) is a member of the Paxillin family of proteins and is an adhesive plaque scaffolding protein. Its expression can be detected in both vascular and smooth muscle cells. Thus, it plays an essential role in vascular remodeling, as well as in fibrotic diseases. Hic‑5 functions as a coactivator of steroid receptors, thus playing a role in steroid hormone‑dependent diseases. It also plays a vital role in the invasive metastasis of various types of cancer. Moreover, several studies have demonstrated that Hic‑5 plays a critical role in transcriptional regulation, as well as in numerous signaling pathways. Therefore, the inhibition of the functions of Hic‑5 may prevent the development or halt the progression of several diseases. Its use as a therapeutic target in future investigations may thus aid in the treatment of several diseases, including various types of cancer. The present review article focused on the expression and functions of Hic‑5 in different organs, with the aim of highlighting novel possibilities for future research.
Topics: Cell Adhesion; Focal Adhesion Protein-Tyrosine Kinases; Hormones; Hydrogen Peroxide; Integrins; Paxillin; Phosphorylation
PubMed: 36222304
DOI: 10.3892/ijmm.2022.5194 -
Oncotarget May 2016Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer in large part due to late diagnosis and a lack of effective screening tests. In spite of recent progress... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer in large part due to late diagnosis and a lack of effective screening tests. In spite of recent progress in imaging, surgery and new therapeutic options for pancreatic cancer, the overall five-year survival still remains unacceptably low. Numerous studies have shown that focal adhesion kinase (FAK) is activated in many cancers including PDAC and promotes cancer progression and metastasis. Paxillin, an intracellular adaptor protein that plays a key role in cytoskeletal organization, connects integrins to FAK and plays a key role in assembly and disassembly of focal adhesions. Here, we have reviewed evidence in support of FAK as a potential therapeutic target and summarized related combinatorial therapies.
Topics: Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Focal Adhesion Kinase 1; Humans; Models, Biological; Molecular Targeted Therapy; Pancreatic Neoplasms; Paxillin; Protein Kinase Inhibitors; Signal Transduction
PubMed: 26980710
DOI: 10.18632/oncotarget.8040 -
Acta Biochimica Polonica Apr 2021Globally, the tenth most common cancer is the oral squamous cell carcinoma (OSCC) and the treatment strategy for improving of OSCC patients survival rate still remains a...
Globally, the tenth most common cancer is the oral squamous cell carcinoma (OSCC) and the treatment strategy for improving of OSCC patients survival rate still remains a challenging one. Aberrant regulation of cell to extracellular matrix protein interactions leads to progression of human cancers. The focal adhesion kinase (FAK) and its downstream target paxillin have been implicated in cancer growth, migration, invasion and metastasis of different cancers. However, the clinical significance of FAK and paxillin in OSCC is not well characterized so far. In the present work, we showed that relative mRNA and protein expressions of FAK and paxillin are significantly higher in side population (SP) cells of OSCC cell line SCC-55. Concomitantly, the matrix metalloproteinase-11 (MMP-11) level is also significantly elevated in SP cells. The enhanced expression of paxillin is strongly correlated with increased chemoresistance, proliferation rate, migration and invasion potential of SP cells. In addition, inhibition of paxillin expression by RNAi makes SP cells more sensitive to chemotherapy drugs. Therefore, our results suggest that paxillin over expression might play a significant role in cancer progression, invasion and chemoresistance of OSCC.
Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Focal Adhesion Protein-Tyrosine Kinases; Humans; Matrix Metalloproteinase 11; Mouth Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Paxillin; RNA Interference; Side-Population Cells
PubMed: 33860659
DOI: 10.18388/abp.2020_5583 -
The Role of Paxillin Aberrant Expression in Cancer and Its Potential as a Target for Cancer Therapy.International Journal of Molecular... May 2023Paxillin is a multi-domain adaptor protein. As an important member of focal adhesion (FA) and a participant in regulating cell movement, paxillin plays an important role... (Review)
Review
Paxillin is a multi-domain adaptor protein. As an important member of focal adhesion (FA) and a participant in regulating cell movement, paxillin plays an important role in physiological processes such as nervous system development, embryonic development, and vascular development. However, increasing evidence suggests that paxillin is aberrantly expressed in many cancers. Many scholars have also recognized that the abnormal expression of paxillin is related to the prognosis, metastases, invasion, survival, angiogenesis, and other aspects of malignant tumors, suggesting that paxillin may be a potential cancer therapeutic target. Therefore, the study of how aberrant paxillin expression affects the process of tumorigenesis and metastasis will help to develop more efficacious antitumor drugs. Herein, we review the structure of paxillin and its function and expression in tumors, paying special attention to the multifaceted effects of paxillin on tumors, the mechanism of tumorigenesis and progression, and its potential role in tumor therapy. We also hope to provide a reference for the clinical prognosis and development of new tumor therapeutic targets.
Topics: Humans; Paxillin; Neoplasms; Cell Movement; Antineoplastic Agents; Carcinogenesis; Cell Line, Tumor
PubMed: 37175948
DOI: 10.3390/ijms24098245 -
Journal of Hematology & Oncology Feb 2017Paxilllin is a multifunctional and multidomain focal adhesion adapter protein which serves an important scaffolding role at focal adhesions by recruiting structural and... (Review)
Review
Paxilllin is a multifunctional and multidomain focal adhesion adapter protein which serves an important scaffolding role at focal adhesions by recruiting structural and signaling molecules involved in cell movement and migration, when phosphorylated on specific Tyr and Ser residues. Upon integrin engagement with extracellular matrix, paxillin is phosphorylated at Tyr31, Tyr118, Ser188, and Ser190, activating numerous signaling cascades which promote cell migration, indicating that the regulation of adhesion dynamics is under the control of a complex display of signaling mechanisms. Among them, paxillin disassembly from focal adhesions induced by extracellular regulated kinase (ERK)-mediated phosphorylation of serines 106, 231, and 290 as well as the binding of the phosphatase PEST to paxillin have been shown to play a key role in cell migration. Paxillin also coordinates the spatiotemporal activation of signaling molecules, including Cdc42, Rac1, and RhoA GTPases, by recruiting GEFs, GAPs, and GITs to focal adhesions. As a major participant in the regulation of cell movement, paxillin plays distinct roles in specific tissues and developmental stages and is involved in immune response, epithelial morphogenesis, and embryonic development. Importantly, paxillin is also an essential player in pathological conditions including oxidative stress, inflammation, endothelial cell barrier dysfunction, and cancer development and metastasis.
Topics: Animals; Cell Movement; Focal Adhesions; Humans; Pathology, Molecular; Paxillin; Phosphorylation; Signal Transduction
PubMed: 28214467
DOI: 10.1186/s13045-017-0418-y -
Journal of Smooth Muscle Research =... 2023Vascular smooth muscle cell (VSMC) migration plays an important role in cardiovascular diseases, including atherosclerotic plaque formation and restenosis after vascular... (Review)
Review
Vascular smooth muscle cell (VSMC) migration plays an important role in cardiovascular diseases, including atherosclerotic plaque formation and restenosis after vascular intervention. The mechanisms involved in VSMC migration are complex and have not been fully elucidated. Recently, we discovered a novel interaction, direct binding of active Fyn-paxillin at focal adhesions, which plays an important role in actin stress fiber formation and migration in VSMCs. In this review, we highlight paxillin as an intermediate signaling molecule that mediates actin stress fiber formation and VSMC migration through the Fyn/paxillin/Rho-kinase signaling pathway by directly binding to active Fyn. We also discuss the inhibition of VSMC migration by blocking the active Fyn-paxillin interaction and the potential of this interaction as a therapeutic target for cardiovascular diseases.
Topics: Humans; Paxillin; Muscle, Smooth, Vascular; Actins; Cardiovascular Diseases; Cell Movement
PubMed: 37438114
DOI: 10.1540/jsmr.59.58 -
Molecular Biology of the Cell Jun 2023Rab GTPase-mediated vesicle trafficking of cell surface proteins, including integrins, through endocytic and recycling pathways is important in controlling...
Rab GTPase-mediated vesicle trafficking of cell surface proteins, including integrins, through endocytic and recycling pathways is important in controlling cell-extracellular matrix interactions during cell migration. The focal adhesion adaptor protein, paxillin, plays a central role in regulating adhesion dynamics and was previously shown to promote anterograde vesicle trafficking through modulation of microtubule acetylation via its inhibition of the deacetylase HDAC6. The role of paxillin in retrograde trafficking is unknown. Herein, we identified a role for paxillin in the modulation of the Rab5 GTPase, which is necessary for regulating early endosome dynamics and focal adhesion turnover. Using MDA-MB-231 breast cancer cells and paxillin (-/-) fibroblasts, paxillin was shown to impact Rab5-associated vesicle size and distribution, as well as Rab5 GTPase activity, through its modulation of HDAC6. Using a combination of real-time imaging and particle tracking analysis, paxillin was shown to promote Rab5-associated vesicle motility through inhibition of HDAC6-mediated micro-tubule deacetylation, along with the localization of active integrin to focal adhesions.
Topics: Humans; Paxillin; Acetylation; Protein Processing, Post-Translational; Cell Movement; Focal Adhesions; Integrins; Microtubules; rab GTP-Binding Proteins; Cell Adhesion
PubMed: 37043310
DOI: 10.1091/mbc.E22-10-0455 -
BMC Biology Nov 2020Extracellular adenosine triphosphate (ATP), a key danger-associated molecular pattern (DAMP) molecule, is released to the extracellular medium during inflammation by...
BACKGROUND
Extracellular adenosine triphosphate (ATP), a key danger-associated molecular pattern (DAMP) molecule, is released to the extracellular medium during inflammation by injured parenchymal cells, dying leukocytes, and activated platelets. ATP directly activates the plasma membrane channel P2X7 receptor (P2X7R), leading to an intracellular influx of K, a key trigger inducing NLRP3 inflammasome activation. However, the mechanism underlying P2X7R-mediated activation of NLRP3 inflammasome is poorly understood, and additional molecular mediators have not been identified. Here, we demonstrate that Paxillin is the molecule connecting the P2X7 receptor and NLRP3 inflammasome through protein interactions.
RESULTS
We show a distinct mechanism by which Paxillin promotes ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome. Extracellular ATP induces Paxillin phosphorylation and then facilitates Paxillin-NLRP3 interaction. Interestingly, Paxillin enhances NLRP3 deubiquitination and activates NLRP3 inflammasome upon ATP treatment and K efflux. Moreover, we demonstrated that USP13 is a key enzyme for Paxillin-mediated NLRP3 deubiquitination upon ATP treatment. Notably, extracellular ATP promotes Paxillin and NLRP3 migration from the cytosol to the plasma membrane and facilitates P2X7R-Paxillin interaction and PaxillinNLRP3 association, resulting in the formation of the P2X7R-Paxillin-NLRP3 complex. Functionally, Paxillin is essential for ATP-induced NLRP3 inflammasome activation in mouse BMDMs and BMDCs as well as in human PBMCs and THP-1-differentiated macrophages.
CONCLUSIONS
We have identified paxillin as a mediator of NLRP3 inflammasome activation. Paxillin plays key roles in ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome by facilitating the formation of the P2X7R-Paxillin-NLRP3 complex.
Topics: Adenosine Triphosphate; Animals; HEK293 Cells; HeLa Cells; Humans; Inflammasomes; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Paxillin; Receptors, Purinergic P2X7
PubMed: 33243234
DOI: 10.1186/s12915-020-00918-w