Gene name - myospheroid
Synonyms - l(1)mys, betaPS
Cytological map position - 7D1-6
Function - adhesion
Keyword(s) - integrin
Symbol - mys
Genetic map position - 1-
Classification - integrin - beta subunit of PS1 & PS2
Cellular location - surface - transmembrane
|Recent literature||Sawala, A., Scarcia, M., Sutcliffe, C., Wilcockson, S. G. and Ashe, H. L. (2015). Peak BMP responses in the Drosophila embryo are dependent on the activation of integrin signaling. Cell Rep 12: 1584-1593. PubMed ID: 26321638
Within a 3D tissue, cells need to integrate signals from growth factors, such as BMPs, and the extracellular matrix (ECM) to coordinate growth and differentiation. This study used the Drosophila embryo as a model to investigate how BMP responses are influenced by a cell's local ECM environment. Integrins, which are ECM receptors, were shown to be absolutely required for peak BMP signaling. This stimulatory effect of integrins requires their intracellular signaling function, which is activated by the ECM protein collagen IV. Mechanistically, integrins interact with the BMP receptor Thickveins and stimulate phosphorylation of the downstream Mad transcription factor. The BMP-pathway-enhancing function of integrins is independent of focal adhesion kinase, but it requires conserved NPXY motifs in the β-integrin cytoplasmic tail. Furthermore, it was shown that an α-integrin subunit is a BMP target gene, identifying positive feedback between integrin signaling and BMP pathway activity that may contribute to robust cell fate decisions.
|Nachman, A., Halachmi, N., Matia, N., Manzur, D. and Salzberg, A. (2015).. Deconstructing the complexity of regulating common properties in different cell types: lessons from the delilah gene. Dev Biol 403: 180-191. PubMed ID: 25989022
To decode how adhesion is regulated in cells stemming from different pedigrees this study analyzed the regulatory region that drives the expression of Delilah, which is a transcription factor that serves as a central determinant of cell adhesion, particularly by inducing expression of βPS-integrin. Activation of dei transcription was shown to be mediated through multiple cis regulatory modules, each driving transcription in a spatially and temporally restricted fashion. Thus the dei gene provides a molecular platform through which cell adhesion can be regulated at the transcriptional level in different cellular milieus. Moreover, these regulatory modules respond, often directly, to central regulators of cell identity in each of the dei-expressing cell types, such as D-Mef2 in muscle cells, Stripe in tendon cells and Blistered in wing intervein cells. These findings suggest that the acquirement of common cellular properties shared by different cell types is embedded within the unique differentiation program dictated to each of these cells by the major determinants of its identity.
|Lee, J. Y., Chen, J. Y., Shaw, J. L. and Chang, K. T. (2016). Maintenance of stem cell niche integrity by a novel activator of integrin signaling. PLoS Genet 12: e1006043. PubMed ID: 27191715
Stem cells depend critically on the surrounding microenvironment, or niche, for their maintenance and self-renewal. While much is known about how the niche regulates stem cell self-renewal and differentiation, mechanisms for how the niche is maintained over time are not well understood. At the apical tip of the Drosophila testes, germline stem cells (GSCs) and somatic stem cells share a common niche formed by hub cells. This study demonstrates that a novel protein named Shriveled (Shv; CG4164) is necessary for the maintenance of hub/niche integrity. Depletion of Shv protein results in age-dependent deterioration of the hub structure and loss of GSCs, whereas upregulation of Shv preserves the niche during aging. Shv is a secreted protein that modulates DE-cadherin levels through extracellular activation of integrin signaling. This work identifies Shv as a novel activator of integrin signaling and suggests a new integration model in which crosstalk between integrin and DE-cadherin in niche cells promote their own preservation by maintaining the niche architecture.
Meehan, T. L., Kleinsorge, S. E., Timmons, A. K., Taylor, J. D. and McCall, K. (2015). Polarization of the epithelial layer and apical localization of integrins are required for engulfment of apoptotic cells. Dis Model Mech [Epub ahead of print]. PubMed ID: 26398951
Inefficient clearance of dead cells or debris by epithelial cells can lead to or exacerbate debilitating conditions such as retinitis pigmentosa, macular degeneration, chronic obstructive pulmonary disease, and asthma. Despite the importance of engulfment by epithelial cells, little is known about the molecular changes that are required within these cells. The misregulation of integrins has previously been associated with disease states, suggesting that a better understanding of the regulation of receptor trafficking may be key to treating diseases caused by defects in phagocytosis. This study demonstrates that the integrin heterodimer αPS3/βPS becomes apically enriched and is required for engulfment by the epithelial follicle cells of the Drosophila ovary. Integrin heterodimer localization and function is largely directed by the α subunit. Moreover, proper cell polarity promotes asymmetric integrin enrichment, suggesting that αPS3/βPS trafficking occurs in a polarized fashion. Several genes previously known for their roles in trafficking and cell migration are also required for engulfment. Moreover, as in mammals, the same α integrin subunit is required by professional and non-professional phagocytes and migrating cells in Drosophila. These findings suggest that migrating and engulfing cells may use common machinery and demonstrate a critical role for integrin function and polarized trafficking of integrin subunits during engulfment. This study also establishes the epithelial follicle cells of the Drosophila ovary as a powerful model for understanding the molecular changes required for engulfment by a polarized epithelium.
|Yeun Lee, J., Geng, J., Lee, J., Wang, A.R. and
Chang, K.T. (2017). Activity-induced
synaptic structural modifications by an activator of integrin signaling
at the Drosophila neuromuscular junction. J Neurosci
[Epub ahead of print]. PubMed ID: 28219985
Activity-induced synaptic structural modification is crucial for neural development and synaptic plasticity, but the molecular players involved in this process are not well defined. This study reports that a protein named Shriveled, Shv, regulates synaptic growth and activity-dependent synaptic remodeling at the Drosophila neuromuscular junction. Depletion of Shv causes synaptic overgrowth and an accumulation of immature boutons. Shv physically and genetically interacts with βPS integrin. Furthermore, Shv is secreted during intense, but not mild, neuronal activity to acutely activate integrin signaling, induce synaptic bouton enlargement, and increase postsynaptic glutamate receptor abundance. Consequently, loss of Shv prevents activity-induced synapse maturation and abolishes post-tetanic potentiation, a form of synaptic plasticity. These data identify Shv as a novel trans-synaptic signal secreted upon intense neuronal activity to promote synapse remodeling through integrin receptor signaling
Integrins are cell surface receptors involved in cell adhesion to other cells and to the extracellular matrix. Cells form multiprotein complexes (adhesion plaques), for which integrins constitute a principle component. Drosophila integrins comprise a multiprotein family consisting of multiple alpha and beta subunits. The first position specific integrins to have been isolated comprise two alpha subunits (alphaPS1 and alphaPS2), and a common beta subunit (betaPS). These three proteins have been named, respectively, Multiple edematous wings (Mew), Inflated (If), and Myospheroid (Mys) (Gotwals, 1994b). The myospheroid gene, isolated by T. W. Wright in the late 1950s, received its name from the tendency of muscles in mutant embryos to detach from their attachment sites (the apodemes) after the muscles have initially made proper attachments, and subsequently round up, i.e. become spheroid.
Each integrin molecule has an alpha chain and a beta chain of amino acids. The alpha and the beta chains combine to form an alpha-beta heterodimer. AlphaPS1 betaPS and alphaPS2 betaPS are the two principle heterodimer combinations of integrins. During gastrulation they first accumulate in embryonic tissues on the basal surface of adjacent ectodermal and presumptive mesodermal layers of the blastoderm, respectively. A specific defect in gastrulation cannot be detected at this stage, but later in germband extention [Images], defects are apparent in about half the mutants. Also apparent is a defective attachment of ectodermal and mesodermal layers. Thus PS integrins appear to play an early role in the integrity of central tissues associated with the germband and in germband extention (Roote, 1994).
Later roles can be detected in the attachment of the amnioserosa [Image] to the hindgut (a region in which MYS is concentrated) and a failure in endoderm migration and midgut constriction. Endoderm forms from the anterior and posterior midgut rudiments, derived mainly from a type of cell termed the principle midgut epithelial cell. Precursors of endothelium from the anterior and posterior midgut rudiments migrate along the visceral mesoderm, changing their shape as they migrate from mesenchymal to epithelial morphology (Tepase, 1994).
PS integrins are concentrated in both the midgut tissue and the surrounding visceral mesoderm. In mys mutants, midgut and mesoderm primordia invaginate normally but remain as spherical cell masses. The cells show little migration toward the center of the embryo (Roote, 1995).
The special role of integrins in wing morphogenesis is reviewed at the apterous site. Integrins whose transcription is regulated by apterous are involved in a compartment-specific role controlling dorsal and ventral compartment integrity (Blair, 1994). Integrins are involved in eye morphogenesis, in a process anchoring rhabdomeres to the cone cell plate (Longley, 1995).
The view of integrins as mere passive hooks mediating cell adhesion events is out of date. Studies in mammalian systems reveal that signaling through integrins results in phosphorylation of a protein tyrosine kinase, known as focal adhesion kinase (FAK) (Lipfert, 1992). Interaction between FAK and Crk-associated tyrosine kinase substrate (CAS) is a consequence of this activation due to interaction with ligand. Activation of FAK results in modification of SCR by FAK and interaction with GRB2 (Polte, 1995). This developmental alphabet soup results in the building up of focal adhesion plaque, the structure by which the cell adheres to substratum. Interactions between the proteins constituting the plaque are distinctly non-linear, and quite complex.
Thus integrins are a major component of the cell's machinery for adherence to substrate (either extracellular matrix or other cells), based on a calcium dependent process that produces a focal adhesion plaque. The process involves signaling between the extracellular domain of integrins and the interior of the cell, with many intracellular responses to the adhesion event.
During embryonic development, there are numerous cases where organ or tissue formation depends upon the migration of primordial cells. In the Drosophila embryo, the visceral mesoderm (vm) acts as a substrate for the migration of several cell populations of epithelial origin, including the endoderm, the trachea and the salivary glands. These migratory processes require both integrins and laminins. The current model is that αPS1βPS (PS1, the heterodimer of Mew and Myospheroid) and/or αPS3βPS (PS3, the heterodimer of Scab and Mys) integrins are required in migrating cells, whereas αPS2βPS (PS2 the heterodimer of Inflated and Mys) integrin is required in the vm, where it performs an as yet unidentified function. This study shows that PS1 integrins are also required for the migration over the vm of cells of mesodermal origin, the caudal visceral mesoderm (CVM). These results support a model in which PS1 might have evolved to acquire the migratory function of integrins, irrespective of the origin of the tissue. This integrin function is highly specific and its specificity resides mainly in the extracellular domain. In addition, the Laminin α1,2 trimer, was identified as the key extracellular matrix (ECM) component regulating CVM migration. Furthermore, this study shows that, as it is the case in vertebrates, integrins, and specifically PS2, contributes to CVM movement by participating in the correct assembly of the ECM that serves as tracks for migration (Urbano, 2011).
Integrin cell surface adhesion receptors play an essential role in mediating cell migration during development. During Drosophila embryogenesis, integrins are implicated in the movement of three groups of epithelial cells over the vm. In all cases, migration requires the function of PS1, and in some cases PS3, in migrating cells and an unknown function for PS2 in the visceral mesoderm. This study shows that PS1 and PS2 integrins are also required for the migration over the vm of cells of mesodermal origin, the longitudinal visceral muscle progenitors or CVM. PS1 is expressed and required in migrating CVM cells and this function is highly specific, as it cannot be replaced by PS2. Furthermore, this specificity lies mainly in the extracellular domain. In addition, the results revealed that a function of PS2 in the vm is to assemble an ECM substrate necessary for migration. This function of PS2 is not specific, as it can be substituted by PS1 (Urbano, 2011).
Previous analysis of the capacities of PS1 and PS2 integrins to substitute for each other in several cellular processes have revealed specific requirements for the different functional abilities of the two integrins. In a classical view, the diversification of the function of a progenitor gene may occur through the partitioning of regulatory sequences in the original duplication event. The differential tissue expression would then lead to functional refinement and diversification. Phylogenetic analyses of α integrins support this model for the PS1 and PS2 families (Hughes, 2001). An ancestral single α subunit would have duplicated to give rise to αPS2, which retained mesodermal regulatory sequences and evolved to perform stable adhesions, and αPS1, which retained ectodermal and endodermal regulatory elements, and became specialized in mediating dynamic adhesions (Martin-Bermudo, 1997). The current results showing that αPS1 is expressed in a mesodermal derivative suggest that the scenario might not be that simple. In an alternative model, protein functional divergence may have preceded changes in expression patterns. After the duplication event, rapid changes in functionally important sequences of the protein may have gradually led to functional divergence. Then, the two duplicate genes might have undergone degeneration of some of their cis-regulatory motifs. In this context, αPS1 would have diverged to perform a migratory function. Finally, coding-sequence and expression divergence between αPS2 and αPS1 could have been coupled (Urbano, 2011).
This study shows that during cell migration, as it is the case for most integrin-dependent developmental events, PS1 and PS2 cannot substitute for each other. The results demonstrate that the specificity resides mainly in the extracellular domain. PS1 and PS2 integrins show distinct binding specificity for all ligands identified to date. Thus, one way to explain why the αPS2 extracellular domain cannot substitute the αPS1 could be that the interaction between PS2 and its own ligand might promote an adhesion that it is not appropriate for cell migration. The cytoplasmic domain of the α subunits plays important roles in specifying responses upon ligand-binding. For example, while α5 and α2 cytoplasmic domains support collagen gel contraction, α4 cytoplasmic domain promotes cell migration on collagen. The demonstration that the αPS2 cytoplasmic tail cannot fully replace the αPS1 tail suggests that during cell migration the cytoplasmic domains may also participate by transmitting distinct intracellular responses. Alternatively, the downstream effectors of PS2 may not be present in migrating cells. Finally, as PS2 has been shown to promote cell spreading on tiggrin, a third explanation could be that the ECM components that serve as PS2 ligands for migration are not present on the vm (Urbano, 2011).
In contrast, this study has shown that αPS2 can be replaced by αPS1 in the vm, as it is the case during the migration of the tracheal cells. This result suggests that PS integrin function during the assembly of an ECM substrate necessary for cell migration does not require specificity of the α subunit. This is also the case for integrin function on the regulation of gene expression in the embryo (Urbano, 2011).
During amphibian gastrulation, integrins contribute to cell movement in several ways. They are required in migrating cells to provide traction and to transmit guidance signals and in the surrounding cells to assemble an ECM substrate that serves as tracks for migration. In Drosophila, integrins have been shown to be required for the assembly of ECM components in several developmental processes, including dorsal closure, wing imaginal disc morphogenesis and maintenance of the stem-cell niche in the gonads. This study shows that in flies, as it is the case in vertebrates, integrins, and in particular PS2, contribute to cell migration by assisting in the assembly of an ECM substrate. PS2, and not PS1, mutant embryos show irregularities in the visceral mesoderm. Thus, there are at least two possible ways in which PS2 could function in the assembly of an ECM over the vm. PS2 could be required for proper morphogenesis of the vm, which in turn could be necessary for proper expression and/or localization of ECM components. Alternatively, PS2 could directly assemble an ECM essential for both cell migration and proper vm morphogenesis (Urbano, 2011).
Experiments in different model systems have demonstrated the importance of the ECM for the migration of different cell populations. It has been shown that removal of all laminins in the Drosophila embryo affects the migration of several cell populations over the vm. This study shows that laminins are also required for the migration of CVM cells. Furthermore, the results demonstrate that lamininW (Wing blister) is the main ECM molecule supporting CVM migration, and that lamininA, perlecan and collagen IV appear of lesser importance. The migration defects observed in embryos mutant for lamininW are more severe than those found in embryos lacking both the PS integrins and Dystroglycan (Dg). One explanation for this result is that other laminin receptors might be required for CVM migration. Alternatively, laminin function during CVM migration may not only be to provide an ECM substratum, but also to present binding sites for guidance cues necessary for CVM migration. Recent studies in Drosophila showing genetic interactions between laminins and the secreted guidance cue Slit during embryonic cardiac cell migration and axons across the midline support this option. This study has also found that Nidogen (Ndg), a glycoprotein that forms a non-covalent complex with laminin and collagen IV, accumulates over the vm at the time of CVM migration. Besides a structural role in the generation and maintenance of basement membranes, Ndg, free of laminins, has its own biological functions that include cell migration. Ndg is required for the migration of trophoblasts cells, neutrophils and Schwann cells. Interestingly, α3β1 integrins, which is most similar to αPS1βPS, seem to mediate this non-structural function of Ndg. A role for Drosophila Ndg in cell migration awaits the isolation of mutants in this gene. Finally, it was shown that the main source of ECM molecules in Drosophila, hemocytes and fat body, do not provide the ECM molecules required for CVM migration, suggesting that there might be an alternative source. The alternative source could be either the vm itself, as lamininW has been detected in this tissue in stage 11 embryos, or the CVM themselves. This is the case for human keratinocytes, which deposit laminin 332 to promote their linear migration (Urbano, 2011).
During embryonic development, many cells use as their migratory routes ECM components found in the interstices and/or basement membrane surrounding different tissues. The interactions between moving cells and ECM components has to be highly coordinated to guide cells towards their final destinations during the process of organogenesis. The understanding of how this is regulated is still rather fragmentary due to the complexity of the cellular and molecular interactions involved. It was recently shown that in the Drosophila embryo, ECM components, such as laminins, are required for the migration of many cell populations, including endoderm, macrophages, salivary glands, trachea and mesodermal cells. Thus, the power of Drosophila as a model system can be used to gain insights into the developmental roles of the cell-ECM interactions during cell migration. In addition, migrating tumour cells destroy and consequently rearrange the ECM that surrounds them in order to promote proliferation and tumour invasion. Thus, a detailed and comprehensive analysis of the role of the different ECM molecules and their regulation during cell migration is important to further understand not only embryonic development but also tumor metastasis (Urbano, 2011).
The gene encoding the Drosophila PS2 alpha subunit is composed of 12 exons spanning 31 kb. By employing a novel method for directed cDNA cloning, over 300 independent cDNA clones were analyzed for the existence of alternate RNA products. Two forms of PS2 alpha mRNA are frequently observed: a canonical (C) form and a form lacking the 75 nucleotide exon 8 (m8). The relative ratio of these two forms varies widely during development. Although region A, derived from exon 8 and the adjacent 25 amino acids, shows weak conservation among the sequences of alpha subunits that bind to different ligands, it is highly conserved in the homologous PS2 alpha gene of the distantly related Mediterranean fruitfly. It is suggested that the variable region A may be important in determining the specificity and affinity of integrin receptors for their ligands (Brown, 1989).
Either of the two alternative spliced forms of the transcript of the mys gene is sufficient to rescue postembryonic mys phenotypes in the wing, eye and muscle but both of the two splice forms are necessary to rescue the mys embryonic defects. The location of the alternative exons suggests that the two forms of the PS beta integrin subunit may interact with alternative alpha subunits and/or ligands (Zusman, 1993).
The Myospheroid protein is an integrin beta subunit of Drosophila. myospheroid cDNA sequence predicts a cysteine-rich integral membrane protein that displays 45% sequence identity to chicken integrin and the human fibronectin receptor beta subunit.
There is a 23 amino acid N-terminal signal sequence and a 23 amino acid hydrophobic membrane-spanning domain starting at amino acid 777. Of the 57 cysteine residues in MYS protein, 56 align with chicken integrin B in four repeated units (MacKrell, 1988). A tyrosine residue at position 834 agrees with consensus sequences of for phosphorylation by protein tyrosine kinases (MacKrell, 1988).
date revised: 2 NOV 97
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