BIOLOGICAL OVERVIEW

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.

PROTEIN STRUCTURE

Amino Acids - 846

Structural Domains

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  

Home page: The Interactive Fly © 1995, 1996 Thomas B. Brody, Ph.D.

The Interactive Fly resides on the
Society for Developmental Biology's Web server.