Disease relevance of Pxn

• Phosphorylation of paxillin via the ERK mitogen-activated protein kinase cascade in EL4 thymoma cells [1].
• We previously demonstrated that phosphorylation of FAK and paxillin is not downregulated in cystic kidneys from B cell lymphoma/leukemia-2 (bcl-2) -/- mice [2].
• Certain aspects of the in vivo signaling phenotype including increased paxillin phosphorylation could be recapitulated in vitro using neonatal rat cardiomyocytes infected with recombinant adenovirus to overexpress tropomodulin [3].
• Protein phosphatase-2A modulates the serine and tyrosine phosphorylation of paxillin in Lewis lung carcinoma tumor variants [4].
• Pasteurella multocida toxin, a potent intracellularly acting mitogen, induces p125FAK and paxillin tyrosine phosphorylation, actin stress fiber formation, and focal contact assembly in Swiss 3T3 cells [5].

High impact information on Pxn

• These contractions leave periodic rows of matrix bound beta3-integrin and paxillin while generating waves of rearward moving actin bound alpha-actinin and MLCK [6].
• These complexes, which are associated with lamellipodia and filopodia, contain vinculin, paxillin, and focal adhesion kinase, but are distinct from and formed independently of rho-induced focal adhesions [7].
• Furthermore, expression of a mutant ILK lacking kinase activity and/or paxillin binding in ILK-deficient fibroblasts can rescue cell spreading, F-actin organization, FA formation, and proliferation [8].
• Expression of paxillin mutants that disrupt ERK association or phosphorylation inhibits HGF-induced cell spreading, migration, and tubulogenesis [9].
• Phosphorylation-dependent paxillin-ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis [10].

Chemical compound and disease context of Pxn

• Using Lewis lung carcinoma (LLC) tumor variants, this study shows the importance of the serine/threonine protein phosphatase-2A (PP-2A) in maintaining adherence and restricting tumor cell motility, and modulating the serine and tyrosine phosphorylation of paxillin [4].
• Pretreatment with the Clostridium botulinum C3 exoenzyme which inactivates p21rho, markedly reduced the ability of GTP gamma S to stimulate tyrosine phosphorylation of M(r) 110,000-130,000 and 70,000-80,000 bands including p125FAK and paxillin in permeabilized Swiss 3T3 cells [11].
• In nonmetastatic Lewis lung carcinoma (LLC) tumor cells, inhibition of the serine/threonine protein phosphatase-2A (PP-2A) activity results in increased motility that is associated with a reduction in the phosphotyrosine content of paxillin [12].

Biological context of Pxn

• Transfection with paxillin Y31FY118F dominant-negative mutant in these cells inhibits ERK activation and restores apoptosis [13].
• Paxillin, a multifunctional docking protein involved in cell adhesion, was phosphorylated on serine/threonine residues in response to PMA treatment [1].
• EphB1-mediated cell migration requires the phosphorylation of paxillin at Tyr-31/Tyr-118 [14].
• Both of these phenotypes are recovered in paxillin knockout cells upon exogenous re-expression of paxillin [15].
• We show by mutagenesis that paxillin binding involves two hydrophobic patches on opposite faces of the bundle and propose a model in which two LD motifs of paxillin adopt amphipathic helices that augment the hydrophobic core of FAT, creating a six-helix bundle [16].

Anatomical context of Pxn

• Hic-5 is a paxillin homologue that is localized to focal adhesion complexes [17].
• In addition, we found that paxillin-null fibroblasts show some defects in the cortical cytoskeleton and cell spreading on fibronectin, raising the possibility that paxillin could play a role in structures distinct from focal adhesions [18].
• Paxillin was found to be critically involved in regulating the development of mesodermally derived structures such as heart and somites [18].
• In the lymphoid cell line BaF3 and the myeloid cell line 32Dcl3, RAFTK coprecipitates with paxillin [19].
• Paxillin is a focal-adhesion associated protein implicated in the regulation of integrin signaling and organization of the actin cytoskeleton [15].

Associations of Pxn with chemical compounds

• We have examined the role of one of the best-characterized integrin effectors, the focal adhesion protein paxillin, by disruption of the paxillin gene in mice [18].
• In vitro, RAFTK could phosphorylate paxillin on tyrosine residues [19].
• Ras-induced serine phosphorylation of the focal adhesion protein paxillin is mediated by the Raf-->MEK-->ERK pathway [20].
• Y-27632, an inhibitor of Rho-associated kinases, prevents tyrosine phosphorylation of focal adhesion kinase and paxillin induced by bombesin: dissociation from tyrosine phosphorylation of p130(CAS) [21].
• Mutation of these serines to alanine, either alone or in combination, inhibited the ability of Raf to induce paxillin phosphorylation [20].

Physical interactions of Pxn

• The results demonstrate that paxillin binding is dispensable for focal adhesion targeting of FAK [22].

Enzymatic interactions of Pxn

• Paxillin was phosphorylated in vitro by purified active ERK2 [1].
• Paxillin was also tyrosine-phosphorylated in Csk-overexpressing cells, indicating that it can serve as a substrate of Csk [23].
• Src and FAK kinases cooperate to phosphorylate paxillin kinase linker, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness [24].

Regulatory relationships of Pxn

• Dissociation of focal adhesion kinase and paxillin tyrosine phosphorylation induced by bombesin and lysophosphatidic acid from epidermal growth factor receptor transactivation in Swiss 3T3 cells [25].
• Paxillin, the target substrate molecule for focal adhesion kinase phosphorylation, was redistributed in tropomodulin-overexpressing transgenic hearts with enhanced paxillin phosphorylation and cleavage [3].
• We found that paxillin was degraded by caspases in Ba/F3 cell apoptosis induced by withdrawal of interleukin-3 (IL-3), a survival factor for this cell, and by ionizing radiation [26].
• The ability of transfected dominant negative Src constructs to inhibit the growth of F4 cells correlated with the inhibition of phosphorylation of paxillin and focal adhesion kinase [27].
• These results indicate that cytostatin inhibits cell adhesion through modification of focal contact proteins such as paxillin by inhibiting a PP2A type protein serine/threonine phosphatase [28].

Other interactions of Pxn

• This increase is shown to result from vinculin's modulation of paxillin-FAK interactions [13].
• Interestingly, tyrosine phosphorylation of paxillin, but not p130cas, was induced by expression of Src-FAT, suggesting a potential role of paxillin in mediating stimulation of cell migration by the chimeric molecule [29].
• Finally, mutation of the Nck-binding site of EphB1 (Y594F) interrupts the interaction between Nck, paxillin, and EphB1 [14].
• The adaptor protein paxillin is essential for normal development in the mouse and is a critical transducer of fibronectin signaling [18].
• Cells transfected with the paxillin mutant Y31F/Y118F displayed a reduced migration in response to ephrin B2 stimulation [14].

Analytical, diagnostic and therapeutic context of Pxn

• Western blot analyses of degradation products of overexpressed green fluorescence protein-tagged paxillin and site-specific mutants demonstrated that Asp-102 and Asp-301 were early caspase cleavage sites, and Asp-5, Asp-146, Asp-165, and Asp-222 were late cleavage sites [26].
• The ability of ARF1 to regulate paxillin recruitment to focal adhesions was confirmed by microinjection of Q71LARF1 and Delta17ARF1 into intact cells [30].
• These proteins were identified as paxillin and FAK, respectively, by immunoprecipitation with anti-paxillin and anti-FAK antibodies [31].
• Immunofluorescence analysis of echistatin treated cells showed the concomitant disappearance of both paxillin and pp125FAK from focal adhesions [32].
• Tracheal constriction studies demonstrate that the level of constriction is the same with knockout of the beta(1)-subunit and BK channel block with paxillin, indicating that BK channels contribute little to airway relaxation in the absence of the beta(1)-subunit [33].

References