Disease relevance of ZYX

• Vinculin did not colocalize with VASP on motile virions and remained in focal adhesion contacts; however, another ABM-1-containing host protein, zyxin, was concentrated at the rear of motile virions [1].
• Zyxin contains a proline-rich N-terminal domain that is similar to the C-terminal domain in the ActA protein of the bacteria, Listeria monocytogenes [2].
• Overexpression of LASP-1 mediates migration and proliferation of human ovarian cancer cells and influences zyxin localisation [3].
• We observe similar phenotypic changes after zyxin gene transfer in SK-N-MC cells, suggesting that zyxin has tumor suppressor activity in Ewing tumor cells [4].
• Silencing of LASP-1 influences zyxin localization, inhibits proliferation and reduces migration in breast cancer cells [5].

High impact information on ZYX

• Here we define the biological activity of the LIM domain through studies of an adhesion plaque protein called zyxin that displays three C-terminal LIM domains [6].
• The diverse array of binding partners for EVH1 domains, including cytoskeletal proteins such as zyxin, transmembrane guidance receptors such as Roundabout, and the T-cell signaling protein Fyb/SLAP, shows that these interactions are likely to be important in a number of cellular processes that require regulated actin filament assembly [7].
• Nuclear targeting of zyxin induces resistance to cell death coincident with nuclear accumulation of activated Akt [8].
• Nuclear accumulation of zyxin and activated Akt may represent a fundamental mechanism that facilitates nuclear-signal transduction and potentiates cell survival [8].
• Thickening of actin stress fibers reflects a cellular adaptation to mechanical stress; this cytoskeletal reinforcement coincides with zyxin mobilization and is abrogated in zyxin-null cells [9].

Biological context of ZYX

• These findings suggest that h-warts/LATS1 and zyxin play a crucial role in controlling mitosis progression by forming a regulatory complex on mitotic apparatus [10].
• On the other hand, the binding site in zyxin is situated at the extreme N terminus as shown by site-directed mutagenesis [11].
• By transfection assays we showed that zyxin interaction with Mena/VASP in vivo enhances the production of actin-rich structures at the apical surface of cells [2].
• Only fragments that were able to dimerize in yeast also bound to zyxin, suggesting that dimerization of alpha-actinin is essential for zyxin binding [12].
• These results indicate that cGK I phosphorylation of VASP results in loss of VASP and zyxin from focal adhesions, a response that could contribute to cGK alteration of cytoskeleton-regulated processes such as cell migration [13].

Anatomical context of ZYX

• The conformational state of Tes regulates its zyxin-dependent recruitment to focal adhesions [14].
• The subcellular distribution, the biochemical properties, as well as microsequencing data revealed that porcine platelet p83 is related to chicken gizzard zyxin and most likely represents the mammalian equivalent of the chicken protein [15].
• Likewise, neither microinjected, fluorescently labeled zyxin antibodies nor ectopically expressed GFP-zyxin were recruited to these latter sites in live cells, whereas both probes incorporated into focal adhesions and stress fibers [16].
• Together, these data identify zyxin as an early target for signals leading to adhesion disassembly, but exclude its role in recruiting Ena/VASP proteins to the tips of lamellipodia and filopodia [16].
• Zyxin is a versatile component of focal adhesions in eukaryotic cells [11].

Associations of ZYX with chemical compounds

• By these blot overlay binding studies, we determined that zyxin interacts with the NH2-terminal 27-kD domain of alpha-actinin, a region that also contains the actin binding site [17].
• The N-terminal proline-rich region of zyxin, which harbors binding sites for alpha-actinin and members of the Ena/VASP family, concentrates in lamellipodial extensions and weakly in focal adhesions [18].
• The human zyxin protein is closely related in sequence to proteins implicated in benign tumorigenesis and steroid receptor binding [19].
• The nuclear accumulation of zyxin occurs asynchronously with approximately half of the cells exhibiting nuclear localization of zyxin within 2.3 h of initiating leptomycin B treatment [18].
• Western immunoblots and confocal experiments with protein synthesis inhibition by cycloheximide confirmed that this difference in distribution of zyxin in migrating versus nonmigrating keratinocytes is due to the redistribution and not upregulation of zyxin [20].
• Accumulation of zyxin at FAs was diminished by blebbistatin, whereas uniaxial stretching of the cells induced zyxin accumulation [21].

Physical interactions of ZYX

• LASP-1 silencing is accompanied by a reduced binding of the LASP-1-binding partner zyxin to focal contacts without changes in actin stress fibre and microtubule organisation or focal adhesion morphology as observed by immunofluorescence [3].
• Screening a mouse embryonic cDNA library with the yeast two-hybrid system shows that Noc2 interacts with the LIM domain-containing protein zyxin, a component of the cytoskeleton, and this interaction is further confirmed by the coimmunoprecipitation experiment [22].
• This association is mediated by the LIM region of the zyxin family members and the SH2 domain-binding region of CasL/HEF1 [23].
• The tumor suppressor Scrib selectively interacts with specific members of the zyxin family of proteins [24].

Regulatory relationships of ZYX

• Treatment of ES cells with zyxin antisense oligonucleotides inhibited CD99-induced cell aggregation and apoptosis, suggesting a functional role for this protein [25].
• MLCK-inhibited cells did not assemble zyxin-containing adhesions at the periphery, but maintained focal adhesions in the center [26].

Other interactions of ZYX

• The COOH-terminal half recruits zyxin as well as Mena and VASP from cell extracts [14].
• Comparing the dynamics of zyxin with that of the focal adhesion protein vinculin revealed that both proteins incorporated simultaneously into newly formed adhesions [16].
• However, during spontaneous or induced focal adhesion disassembly, zyxin delocalization preceded that of either vinculin or paxillin [16].
• Analysis of the alpha-actinin/zyxin interaction [12].
• LPP, an actin cytoskeleton protein related to zyxin, harbors a nuclear export signal and transcriptional activation capacity [27].

Analytical, diagnostic and therapeutic context of ZYX

• The reduction in Mena/VASP binding was confirmed by peptide tests, immunoprecipitation, and ectopic expression of zyxin variants at the surface of mitochondria [2].
• Molecular dissection of zyxin function reveals its involvement in cell motility [28].
• Zyxin displays the architectural features of an intracellular signal transducer [29].
• Antibodies raised against human zyxin recognize an 84-kDa protein by Western immunoblot analysis [19].
• Using this method, we show that decreasing cellular traction forces on focal adhesions by three different techniques--chemical inhibition of cytoskeletal tension generation, laser incision of an associated actin stress fiber, or use of compliant extracellular matrices--increases the k(OFF) of the focal adhesion protein zyxin [30].

References