InteractiveFly: GeneBrief

Zyxin: Biological Overview | References


Gene name - Zyxin

Synonyms - Zyx102

Cytological map position - 102F7-102F8

Function - cytoskeletal signaling protein

Keywords - Hippo pathway, cytoskeletal regulation of growth, transduction of mechanical tension, component of adherens junctions and focal adhesion junctions

Symbol - Zyx

FlyBase ID: FBgn0011642

Genetic map position - chr4:1,057,365-1,065,001

Classification - Lim domain protein

Cellular location - cytoplasmic



NCBI links: Precomputed BLAST | EntrezGene
BIOLOGICAL OVERVIEW

Coordinated multicellular growth during development is achieved by the sensing of spatial and nutritional boundaries. The conserved Hippo (Hpo) signaling pathway has been proposed to restrict tissue growth by perceiving mechanical constraints through actin cytoskeleton networks. The actin-associated LIM proteins Zyxin (Zyx) and Ajuba (Jub) have been linked to the control of tissue growth via regulation of Hpo signaling, but the study of Zyx has been hampered by a lack of genetic tools. A zyx mutant was generated in Drosophila using TALEN endonucleases, and this was used to show that Zyx antagonizes the FERM-domain protein Expanded (Ex) to control tissue growth, eye differentiation, and F-actin accumulation. Zyx membrane targeting promotes the interaction between the transcriptional co-activator Yorkie (Yki) and the transcription factor Scalloped (Sd), leading to activation of Yki target gene expression and promoting tissue growth. Finally, this study shows that Zyx's growth-promoting function is dependent on its interaction with the actin-associated protein Enabled (Ena) via a conserved LPPPP motif and is antagonized by Capping Protein (CP). These results show that Zyx is a functional antagonist of Ex in growth control and establish a link between actin filament polymerization and Yki activity (Gaspar, 2015).

The control of tissue size represents a major unsolved question in developmental biology. The conserved Hippo (Hpo) signaling pathway is thought to sense mechanical and nutritional cues to restrict tissue growth. Activation of the Ste20-like kinase Hpo (MST1/2 in mammals) and subsequent phosphorylation of the downstream Ndr-like kinase Warts (Wts-LATS1/2 in mammals) inhibits the transcriptional co-activator Yorkie (Yki-YAP/TAZ in mammals), via phosphorylation at S168. This prevents the interaction of Yki with transcription factor partners, such as Scalloped (Sd-TEAD1-4 in mammals), thereby inhibiting expression of pro-growth and survival genes (Gaspar, 2015).

The known upstream stimuli for Hpo signaling involve a number of regulatory proteins, many of which are associated with the actin cytoskeleton. In particular, the Drosophila proteins Expanded (Ex) and Merlin (Mer), which belong to the FERM (Four point one, Ezrin, Radixin, Moesin) domain family, and the protocadherins Fat (Ft) and Dachsous (Ds), were identified as tumor suppressors that prevent expression of Yki target genes. Whether Ex/Mer and Ft/Ds signaling represent entirely distinct branches of Hpo signaling remains unclear. For instance, Ft depletion leads to a reduction in apical Ex localization. However, Ft and Ex have been implicated in distinct functions: Ft/Ds are involved in the control of planar cell polarity (PCP), while Ex has strong effects on eye differentiation. The proposed mechanisms of Ft and Ex function are also distinct. In particular, Ex promotes cytoplasmic sequestration of Yki through direct binding and by promoting Hpo-Wts kinase activity, while Ft antagonizes the growth-promoting function of the atypical myosin Dachs (D), which, in turn, destabilizes Wts (Gaspar, 2015).

Several reports have highlighted the contribution of the actin cytoskeleton to Hpo signaling. The actin Capping Protein αβ heterodimer (CP), which prevents addition of actin monomers to F-actin barbed ends, antagonizes Yki activity, and thereby restricts tissue growth. Accordingly, in mammals, CapZ and other factors that restrict F-actin levels, have growth-restrictive effects via the control of YAP/TAZ subcellular localization, particularly in response to mechanical cues. Interestingly, YAP and TAZ respond to mechanical cues dependent on actomyosin networks and formin-dependent actin polymerization. Recently, the actin-associated LIM (Lin11, Isl-1, and Mec-3) domain protein Zyxin (Zyx) has been shown to mediate the effects of Ft-Ds signaling on Yki target genes, by promoting Wts destabilization via its interaction with D (Rauskolb, 2011). Importantly, Zyx provides a link to the actin polymerization machinery, since it directly interacts with the actin-binding proteins Enabled (Ena)/VASP via conserved F/LPPPP motifs, and promotes Ena function in barbed-end F-actin polymerization (Golsteyn, 1997; Drees, 1999; Drees, 2000; Fradelizi, 2001 Gaspar, 2015 and references therein).

The analysis of Drosophila zyx has been limited by the absence of a mutant. This study generated a zyx mutation and describe its effects on growth and Hpo signaling. Zyx is shown to strongly antagonize Ex function in growth control, eye differentiation and F-actin accumulation, while being largely dispensable for Ft-mediated tissue growth. Finally, this work suggests that Zyx's growth-promoting function requires its ability to bind the actin polymerization factor Ena (Gaspar, 2015).

Zyx was previously shown to promote Wts degradation in a mechanism based on a Zyx/Dachs interaction (Rauskolb, 2011). However, this study reports that zyx and dachs (d) have additive effects on tissue growth. In addition, zyx loss has a modest effect on ft growth phenotypes, which, in contrast, are highly sensitive to d mutations, highlighting the possibility of additional functions for Zyx in tissue growth (Gaspar, 2015).

Characterization of the zyx mutant shows that Zyx acts in the Ex branch of the Hpo pathway to control tissue growth. This is in contrast to a previous study using RNAi knockdown of zyx and ex, which concluded that zyx expression had only minor effects on the Ex branch (Rauskolb, 2011). The current results indicate that zyx loss can significantly reverse the lethality and growth defects of ex mutant animals. This antagonistic function of Ex and Zyx is not confined to growth regulation but extends to tissue differentiation. This study shows that Zyx restricts eye differentiation antagonistically to Ex and in parallel to Dachs but independently of Ft. Consistent with these observations, simultaneous loss of ex and ft leads to additive, and therefore apparently independent effects on eye differentiation. Therefore, it is proposed that Zyx is a key modulator of Ex function (Gaspar, 2015).

In growth control, Zyx function may be partially independent of Hpo-Wts signaling, as zyx is partially required for the overgrowth of hpo and wts mutant eye and wing but has no major effect on wts overexpression in the wing or Yki phosphorylation by Wts. Ex has been reported to sequester Yki in the cytoplasm through a direct interaction. However, since ex mutant overgrowth is suppressed by zyx loss, it is unlikely that Zyx directly antagonizes Ex protein. Instead, it is suggested that the interplay between Zyx and Ex in growth control is mediated through their antagonistic effects on F-actin (Gaspar, 2015).

This work links F-actin barbed-end polymerization with Zyx/Ex in the control of Yki activity and tissue growth. The Zyx domain encompassing the conserved LPPPP motif, which binds Ena, is required for Zyx to promote growth and to antagonize Ex function. Moreover, Zyx and Ena synergize to promote tissue growth. This supports the idea that Zyx promotes tissue growth via its interaction with Ena. Conversely, CP antagonizes Zyx-induced tissue growth and functions together with Ex in preventing F-actin polymerization (Fernández, 2011). Therefore, an attractive possibility is that antagonistic effects on Yki activity between the activators Zyx/Ena on one hand and the inhibitors Ex and CP on the other hand is played out indirectly through their effects on F-actin polymerization. Consistent with this hypothesis, Zyx antagonizes the effect of Ex on apical F-actin accumulation (Gaspar, 2015).

Recent data suggest that the actin cytoskeleton acts in parallel to the core kinase cascade to control YAP/TAZ activity, with CapZ being proposed as one of the 'gatekeepers' restricting its nuclear translocation (Aragona, 2013). Yki/YAP/TAZ may respond to the relative activities of Ena and CP, either by being sensitive to the presence of polymerizing actin barbed ends, or because Ena produces a specialized set of cortical actin filaments necessary for Yki/YAP/TAZ activation. The study of the mechanism(s) coupling F-actin and Yki/YAP/TAZ should resolve these issues. This study has shown that Zyx cortical localization is relevant for its function in promoting tissue growth. Since Zyx has been shown to rapidly relocalize to strained or severed actin filaments in cultured mammalian cells (Yoshigi, 2005; Smith, 2010) and Drosophila follicular epithelial cells (Colombelli, 2009), it is possible that Zyx may also link mechanical forces to growth control (Gaspar, 2015).

Finally, it is also interesting to note the possible redundancy in growth control between Zyx and other Ena-interacting proteins. Like Zyx, Pico/Lamellipodin contains an EVH1-interacting L/FPPPP motif, and its interaction with Ena promotes tissue growth in Drosophila (Ribeiro, 2010). Since Ena localization is not strictly dependent on Zyx, it is tempting to speculate that Ena recruitment by multiple membrane-associated proteins, such as Zyx and Pico, is a common denominator in the regulation of growth by the actin cytoskeleton (Gaspar, 2015).

Zyxin links fat signaling to the hippo pathway

The Hippo signaling pathway has a conserved role in growth control and is of fundamental importance during both normal development and oncogenesis. Despite rapid progress in recent years, key steps in the pathway remain poorly understood, in part due to the incomplete identification of components. Through a genetic screen, this study identified the Drosophila Zyxin family gene, Zyx102 (Zyx), as a component of the Hippo pathway. Zyx positively regulates the Hippo pathway transcriptional co-activator Yorkie, as its loss reduces Yorkie activity and organ growth. Through epistasis tests, the requirement for Zyx was positioned within the Fat branch of Hippo signaling, downstream of Fat and Dco, and upstream of the Yorkie kinase Warts, and Zyx was found to be required for the influence of Fat on Warts protein levels. Zyx localizes to the sub-apical membrane, with distinctive peaks of accumulation at intercellular vertices. This partially overlaps the membrane localization of the myosin Dachs, which has similar effects on Fat-Hippo signaling. Co-immunoprecipitation experiments show that Zyx can bind to Dachs and that Dachs stimulates binding of Zyx to Warts. This study also extended characterization of the Ajuba LIM protein Jub and determined that although Jub and Zyx share C-terminal LIM domains, they regulate Hippo signaling in distinct ways. The results identify a role for Zyx in the Hippo pathway and suggest a mechanism for the role of Dachs: because Fat regulates the localization of Dachs to the membrane, where it can overlap with Zyx, it is proposed that the regulated localization of Dachs influences downstream signaling by modulating Zyx-Warts binding. Mammalian Zyxin proteins have been implicated in linking effects of mechanical strain to cell behavior. This identification of Zyx as a regulator of Hippo signaling thus also raises the possibility that mechanical strain could be linked to the regulation of gene expression and growth through Hippo signaling (Rauskolb, 2011).

This characterization of Zyx identifies a role for it as a novel and integral component of the Hippo pathway, which is required for the Fat branch, but not the Ex branch, of Hippo signaling. Unlike most previously identified components, loss of Zyx reduces the activity of the key transcriptional effector of the pathway, Yki, and consequently its loss reduces organ growth. Genetic epistasis experiments position the requirement for Zyx in between fat and wts, and concordant protein binding experiments identify a Dachs-stimulated ability of Zyx to bind Wts protein. In is inferred that this association of Zyx with Wts then downregulates Wts, at least in part, by targeting it for degradation (Rauskolb, 2011).

Zyx localizes to the sub-apical membrane independently of Fat or Dachs. Since Fat regulates the localization of Dachs, this regulated localization provides a mechanism by which Fat could modulate the interaction of Dachs with Zyx (although it is noted that Fat might affect the activity of Dachs in addition to affecting its localization). Since Dachs stimulates Zyx-Wts binding, this regulated localization provides a means for Fat signaling to modulate Zyx-Wts binding. It is inferred that Dachs effects a conformational change in Zyx, as in the absence of Dachs a Zyx LIM-domains polypeptide binds efficiently to Wts, whereas full-length Zyx binds poorly. Intriguingly, the association of vertebrate homologues of Zyx and Warts can also be post-translationally regulated, as the ability of the LIM domains of human LATS1 to bind Zyxin is masked within full-length Zyxin, but uncovered by Cdc2-mediated phosphorylation, presumably due to conformational change (Hirota, 2000). It is hypothesized that the ability of Dachs to bind to both the N-terminus and the LIM domains of Zyx enables it to effect a conformational change in Zyx, resulting in an open configuration that can bind to Wts. It is also possible that Dachs binding stimulates a post-translational modification of Zyx to induce a conformational change (Rauskolb, 2011).

Prior studies identified two mechanisms by which Fat signaling could influence Yki activity, as fat mutation reduces both the levels of Wts protein and the amount of Ex at the sub-apical membrane. It has not been possible to completely uncouple these two pathways for Fat-Hippo signaling, although the observation that over-expression of Wts can efficiently suppress fat overgrowth phenotypes, but only partially suppresses ex overgrowth phenotypes, suggested that the influence of Fat on Wts levels might be more critical. Analysis of the influence of Zyx on Ex is complicated by its influence on ex transcription, but the current observation that reduction of Zyx does not appear to suppress the influence of fat on Ex staining, even though it does suppress the influence of fat on Wts levels, also suggests that the influence of Fat on Wts levels might be more critical than its effects on Ex. Intriguingly, mutation of dachs did suppress the influence of fat on Ex levels. Although it is possible that this difference between dachs and Zyx results from technical differences in the experimental paradigms (e.g., mutant clones versus RNAi), it is also possible that dachs can influence Ex levels independently from its association with Zyx (Rauskolb, 2011).

The discovery of the Fat-specific effect on Wts levels, by contrast to the Hippo-pathway-mediated effect on Wts kinase activity, established the concept of distinct mechanisms for regulating Wts -- one mechanism that affects Wts levels and another that affects Wts activity. This study's identification of distinct genetic requirements for Zyx and Jub provide further support for this concept. As Jub is equally required for both Fat-Hippo and Ex-Hippo signaling and acts genetically between hippo and wts, Jub appears to inhibit Wts activation. In the current working model, the epistasis of Jub to fat could be explained by an increased activity of residual Wts, which then acts catalytically to repress Yki activity. Zyx is required for the influence of fat on Wts levels. It is noted that when measured within a whole tissue lysate, Wts levels are only reduced to approximately half their normal levels. However, as Wts appears to function within multi-protein complexes, including some components that can localize preferentially to the sub-apical membrane, it is hypothesized that Fat signaling affects a discrete pool of Wts within a complex at the membrane that is crucial for Hippo signaling, whereas there might be additional pools of Wts within the cell that are unaffected. It is also noted that while effects on Wts protein levels are clearly seen, the results do not exclude the possibility that Fat signaling also influences Wts activity (Rauskolb, 2011).

The characterization of Zyx and Jub also provides new tools for analyzing critical steps in Hippo signaling. For example, in addition to influencing Hpo and Wts kinase activity, it has been observed that Ex can bind directly to Yki and that when Ex is over-expressed it can repress Yki through a mechanism that involves direct sequestration of Yki, rather than regulation of Yki phosphorylation (Oh, 2009). Because this direct repression mechanism was based on over-expression experiments, the extent to which it contributes to normal Yki regulation in vivo remained uncertain. The observations that Jub acts genetically upstream of wts, yet is required for ex phenotypes, suggests that Ex regulates Yki principally through its effects on Wts activity, rather than through direct interaction with Yki (Rauskolb, 2011).

The ability of Zyx LIM domains to interact with Wts is conserved in their human homologues (Hirota, 2001). Although the functional significance of this interaction in vertebrates has not yet been established, the observations raise the possibility that the oncogenic effects of human LPP mutations could be due to an ability of these aberrant LPP fusion proteins to negatively regulate LATS proteins, resulting in inappropriate activation of YAP or TAZ (Rauskolb, 2011).

One of the most intriguing aspects of Zyxin family proteins is their role in mediating effects of mechanical force on cell behavior (Hirata, 2008). Zyxin family proteins can localize to focal adhesions of cultured fibroblasts, and this localization is modulated by mechanical tension (Beckerle, 1997; Hirata, 2008; Smith, 2010). The observation that increasing tension on stress fibers stimulates Zyxin accumulation at focal adhesions is intriguing in light of the observation that Zyx tends to accumulate at higher levels at intercellular vertices in imaginal discs, as these could be points of increased tension. As the association of unconventional myosins with F-actin can also be influenced by external force (Woolner, 2009), this study's discovery of binding between a myosin protein (Dachs) and Zyx raises the possibility that other myosins might also interact with Zyxin family proteins, which could potentially influence either their tension-based recruitment or their activity (Rauskolb, 2011).

Finally, it is noted that theoretical models of growth control in developing tissues have proposed that growth should be controlled by mechanical tension (Shraiman, 2005; Aegerter-Wilmsen, 2008), and direct evidence for mechanical effects on growth has been obtained in cultured cell models (Nelson, 2005). However, a mechanism for how this might be achieved has been lacking. The discovery that Zyx, a member of a family of proteins implicated in responding to and transducing the effects of mechanical tension, is also a component of the Hippo signaling pathway, a crucial regulator of growth from Drosophila to humans, raises the intriguing possibility that Zyxin family proteins might form part of a molecular link between mechanical tension and the control of growth (Rauskolb, 2011).

The cytoskeletal regulator zyxin is required for viability in Drosophila melanogaster

The zyxin family of proteins function as cytoskeletal regulators in adhesion, actin assembly, and cell motility. Though fibroblasts derived from zyxin-null mice show striking defects in motility and response to mechanical stimuli, the mice are viable and fertile. In Drosophila melanogaster, the family is represented by a single homologue, Zyx102. To study the role of zyxin during development, a zyx102 RNA-interference transgenic line was generated that allows for the conditional knockdown of Zyx102. When UAST-zyx102-dsRNAi expression is driven broadly by Actin5C-GAL4, loss of Zyx102 results in lethality during the pharate adult stage, a narrow developmental window during which the fly must molt, resorb molting fluid, fill adult trachea with air, and execute a behavioral program to eclose. Zyx102 knockdown animals attempt to emerge, but their adult trachea do not fill with air. If dissected from the pupal case, knockdown individuals appear morphologically normal, but remain inviable (Renfranz, 2010).

Mechanosensing in actin stress fibers revealed by a close correlation between force and protein localization

The mechanics of the actin cytoskeleton have a central role in the regulation of cells and tissues, but the details of how molecular sensors recognize deformations and forces are elusive. By performing cytoskeleton laser nanosurgery in cultured epithelial cells and fibroblasts, this study shows that the retraction of stress fibers (SFs) is restricted to the proximity of the cut and that new adhesions form at the retracting end. This suggests that SFs are attached to the substrate. A new computational model for SFs confirms this hypothesis and predicts the distribution and propagation of contractile forces along the SF. The dynamics of zyxin, a focal adhesion protein present in SFs, were analyzed. Fluorescent redistribution after laser nanosurgery and drug treatment shows a high correlation between the experimentally measured localization of zyxin and the computed localization of forces along SFs. Correlative electron microscopy reveals that zyxin is recruited very fast to intermediate substrate anchor points that are highly tensed upon SF release. A similar acute localization response is found if SFs are mechanically perturbed with the cantilever of an atomic force microscope. If actin bundles are cut by nanosurgery in living Drosophila egg chambers, it was also found that zyxin redistribution dynamics correlate to force propagation and that zyxin relocates at tensed SF anchor points, demonstrating that these processes also occur in living organisms. In summary, this quantitative analysis shows that force and protein localization are closely correlated in stress fibers, suggesting a very direct force-sensing mechanism along actin bundles (Colombelli, 2009).

Molecular and phylogenetic characterization of Zyx102, a Drosophila orthologue of the zyxin family that interacts with Drosophila Enabled

Adherens junctions, which are cadherin-mediated junctions between cells, and focal adhesions, which are integrin-mediated junctions between cells and the extracellular matrix, are protein complexes that link the actin cytoskeleton to the plasma membrane and, in turn, to the extracellular environment. Zyxin is a LIM domain protein that is found in vertebrate adherens junctions and focal adhesions. Zyxin's molecular architecture and binding partner repertoire suggest roles in actin assembly and dynamics, cell motility, and nuclear-cytoplasmic communication. In order to study the function of zyxin in development, a zyxin orthologue was identified in Drosophila melanogaster that was termed Zyx102. Like its vertebrate counterparts, Zyx102 displays three carboxy-terminal LIM domains, a potential nuclear export signal, and three proline-rich motifs, one of which matches the consensus for mediating an interaction with Ena/VASP (Drosophila Enabled/Vasodilator-stimulated phosphoprotein) proteins. Zyx102 and Enabled (Ena), the Drosophila member of the Ena/VASP family, can interact specifically in vitro, and this interaction does not occur when a particular mutant form of Ena, encoded by the lethal ena210 allele, is used. The zyx102 gene and Drosophila Ena are co-expressed during oogenesis and early embryogenesis, indicating that the two proteins may be able to interact during the development of the Drosophila egg chamber and early embryo (Renfranz, 2003).

The conserved LIM domain-containing focal adhesion protein ZYX-1 regulates synapse maintenance in Caenorhabditis elegans

This study describes the identification of zyxin as a regulator of synapse maintenance in mechanosensory neurons in C. elegans. zyx-1 mutants lacked PLM mechanosensory synapses as adult animals. However, most PLM synapses initially formed during development but were subsequently lost as the animals developed. Vertebrate zyxin regulates cytoskeletal responses to mechanical stress in culture. This work provides in vivo evidence in support of such a role for zyxin. In particular, zyx-1 mutant synaptogenesis phenotypes were suppressed by disrupting locomotion of the mutant animals, suggesting that zyx-1 protects mechanosensory synapses from locomotion-induced forces. In cultured cells, zyxin is recruited to focal adhesions and stress fibers via C-terminal LIM domains and modulates cytoskeletal organization via the N-terminal domain. The synapse-stabilizing activity was mediated by a short isoform of ZYX-1 containing only the LIM domains. Consistent with this notion, PLM synaptogenesis was independent of alpha-actinin and ENA-VASP, both of which bind to the N-terminal domain of zyxin. These results demonstrate that the LIM domain moiety of zyxin functions autonomously to mediate responses to mechanical stress and provide in vivo evidence for a role of zyxin in neuronal development (Luo, 2014).

Stretch-induced actin remodeling requires targeting of zyxin to stress fibers and recruitment of actin regulators

Reinforcement of actin stress fibers in response to mechanical stimulation depends on a posttranslational mechanism that requires the LIM protein zyxin. The C-terminal LIM region of zyxin directs the force-sensitive accumulation of zyxin on actin stress fibers. The N-terminal region of zyxin promotes actin reinforcement even when Rho kinase is inhibited. The mechanosensitive integrin effector p130Cas binds zyxin but is not required for mitogen-activated protein kinase-dependent zyxin phosphorylation or stress fiber remodeling in cells exposed to uniaxial cyclic stretch. alpha-Actinin and Ena/VASP proteins bind to the stress fiber reinforcement domain of zyxin. Mutation of their docking sites reveals that zyxin is required for recruitment of both groups of proteins to regions of stress fiber remodeling. Zyxin-null cells reconstituted with zyxin variants that lack either alpha-actinin or Ena/VASP-binding capacity display compromised response to mechanical stimulation. These findings define a bipartite mechanism for stretch-induced actin remodeling that involves mechanosensitive targeting of zyxin to actin stress fibers and localized recruitment of actin regulatory machinery (Hoffman, 2012).

Mechanical force mobilizes zyxin from focal adhesions to actin filaments and regulates cytoskeletal reinforcement

Organs and tissues adapt to acute or chronic mechanical stress by remodeling their actin cytoskeletons. Cells that are stimulated by cyclic stretch or shear stress in vitro undergo bimodal cytoskeletal responses that include rapid reinforcement and gradual reorientation of actin stress fibers; however, the mechanism by which cells respond to mechanical cues has been obscure. This study reports that the application of either unidirectional cyclic stretch or shear stress to cells results in robust mobilization of zyxin from focal adhesions to actin filaments, whereas many other focal adhesion proteins and zyxin family members remain at focal adhesions. Mechanical stress also induces the rapid zyxin-dependent mobilization of vasodilator-stimulated phosphoprotein from focal adhesions to actin filaments. 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. These findings identify zyxin as a mechanosensitive protein and provide mechanistic insight into how cells respond to mechanical cues (Yoshigi, 2005).

Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor

The mitotic apparatus plays a pivotal role in dividing cells to ensure each daughter cell receives a full set of chromosomes and complement of cytoplasm during mitosis. A human homologue of the Drosophila warts tumor suppressor, h-warts/LATS1, is an evolutionarily conserved serine/threonine kinase and a dynamic component of the mitotic apparatus. This study identified an interaction of h-warts/LATS1 with zyxin, a regulator of actin filament assembly. Zyxin is a component of focal adhesion, however, during mitosis a fraction of cytoplasmic-dispersed zyxin becomes associated with h-warts/LATS1 on the mitotic apparatus. Zyxin was found to be phosphorylated specifically during mitosis, most likely by Cdc2 kinase, and that the phosphorylation regulates association with h-warts/LATS1. Furthermore, microinjection of truncated h-warts/LATS1 protein, including the zyxin-binding portion, interfered with localization of zyxin to mitotic apparatus, and the duration of mitosis of these injected cells was significantly longer than that of control cells. 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 (Hirota, 2000).


REFERENCES

Search PubMed for articles about Drosophila Zyxin

Aegerter-Wilmsen, T., Aegerter, C. M., Hafen, E. and Basler, K. (2007). Model for the regulation of size in the wing imaginal disc of Drosophila. Mech Dev 124: 318-326. PubMed ID: 17293093

Aragona, M., Panciera, T., Manfrin, A., Giulitti, S., Michielin, F., Elvassore, N., Dupont, S. and Piccolo, S. (2013). A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154: 1047-1059. PubMed ID: 23954413

Beckerle, M. C. (1997). Zyxin: zinc fingers at sites of cell adhesion. Bioessays 19: 949-957. PubMed ID: 9394617

Colombelli, J., Besser, A., Kress, H., Reynaud, E. G., Girard, P., Caussinus, E., Haselmann, U., Small, J. V., Schwarz, U. S. and Stelzer, E. H. (2009). Mechanosensing in actin stress fibers revealed by a close correlation between force and protein localization. J Cell Sci 122: 1665-1679. PubMed ID: 19401336

Drees, B. E., Andrews, K. M. and Beckerle, M. C. (1999). Molecular dissection of zyxin function reveals its involvement in cell motility. J Cell Biol 147: 1549-1560. PubMed ID: 10613911

Drees, B., Friederich, E., Fradelizi, J., Louvard, D., Beckerle, M. C. and Golsteyn, R. M. (2000). Characterization of the interaction between zyxin and members of the Ena/vasodilator-stimulated phosphoprotein family of proteins. J Biol Chem 275: 22503-22511. PubMed ID: 10801818

Fradelizi, J., Noireaux, V., Plastino, J., Menichi, B., Louvard, D., Sykes, C., Golsteyn, R. M. and Friederich, E. (2001). ActA and human zyxin harbour Arp2/3-independent actin-polymerization activity. Nat Cell Biol 3: 699-707. PubMed ID: 11483954

Gaspar, P., Holder, M. V., Aerne, B. L., Janody, F. and Tapon, N. (2015). Zyxin antagonizes the FERM protein Expanded to couple F-actin and Yorkie-dependent organ growth. Curr Biol 25: 679-689. PubMed ID: 25728696

Golsteyn, R. M., Beckerle, M. C., Koay, T. and Friederich, E. (1997). Structural and functional similarities between the human cytoskeletal protein zyxin and the ActA protein of Listeria monocytogenes. J Cell Sci 110 ( Pt 16): 1893-1906. PubMed ID: 9296389

Hirata, H., Tatsumi, H. and Sokabe, M. (2008). Zyxin emerges as a key player in the mechanotransduction at cell adhesive structures. Commun Integr Biol 1: 192-195. PubMed ID: 19513257

Hirota, T., Morisaki, T., Nishiyama, Y., Marumoto, T., Tada, K., Hara, T., Masuko, N., Inagaki, M., Hatakeyama, K. and Saya, H. (2000). Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor. J Cell Biol 149: 1073-1086. PubMed ID: 10831611

Hoffman, L. M., Jensen, C. C., Chaturvedi, A., Yoshigi, M. and Beckerle, M. C. (2012). Stretch-induced actin remodeling requires targeting of zyxin to stress fibers and recruitment of actin regulators. Mol Biol Cell 23: 1846-1859. PubMed ID: 22456508

Luo, S., Schaefer, A. M., Dour, S. and Nonet, M. L. (2014). The conserved LIM domain-containing focal adhesion protein ZYX-1 regulates synapse maintenance in Caenorhabditis elegans. Development 141: 3922-3933. PubMed ID: 25252943

Nelson, C. M., Jean, R. P., Tan, J. L., Liu, W. F., Sniadecki, N. J., Spector, A. A. and Chen, C. S. (2005). Emergent patterns of growth controlled by multicellular form and mechanics. Proc Natl Acad Sci U S A 102: 11594-11599. PubMed ID: 16049098

Oh, H., Reddy, B. V. and Irvine, K. D. (2009). Phosphorylation-independent repression of Yorkie in Fat-Hippo signaling. Dev Biol 335: 188-197. PubMed ID: 19733165

Rauskolb, C., Pan, G., Reddy, B. V., Oh, H. and Irvine, K. D. (2011). Zyxin links fat signaling to the hippo pathway. PLoS Biol 9: e1000624. PubMed ID: 21666802

Renfranz, P. J., Siegrist, S. E., Stronach, B. E., Macalma, T. and Beckerle, M. C. (2003). Molecular and phylogenetic characterization of Zyx102, a Drosophila orthologue of the zyxin family that interacts with Drosophila Enabled. Gene 305: 13-26. PubMed ID: 12594038

Renfranz, P. J., Blankman, E. and Beckerle, M. C. (2010). The cytoskeletal regulator zyxin is required for viability in Drosophila melanogaster. Anat Rec (Hoboken) 293: 1455-1469. PubMed ID: 20648572

Ribeiro, P. S., Josue, F., Wepf, A., Wehr, M. C., Rinner, O., Kelly, G., Tapon, N. and Gstaiger, M. (2010). Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling. Mol Cell 39: 521-534. PubMed ID: 20797625

Shraiman, B. I. (2005). Mechanical feedback as a possible regulator of tissue growth. Proc Natl Acad Sci U S A 102: 3318-3323. PubMed ID: 15728365

Smith, M. A., Blankman, E., Gardel, M. L., Luettjohann, L., Waterman, C. M. and Beckerle, M. C. (2010). A zyxin-mediated mechanism for actin stress fiber maintenance and repair. Dev Cell 19: 365-376. PubMed ID: 20833360

Woolner, S. and Bement, W. M. (2009). Unconventional myosins acting unconventionally. Trends Cell Biol 19: 245-252. PubMed ID: 19406643

Yoshigi, M., Hoffman, L. M., Jensen, C. C., Yost, H. J. and Beckerle, M. C. (2005). Mechanical force mobilizes zyxin from focal adhesions to actin filaments and regulates cytoskeletal reinforcement. J Cell Biol 171: 209-215. PubMed ID: 16247023


Biological Overview

date revised: 22 October 2015

Home page: The Interactive Fly © 2011 Thomas Brody, Ph.D.