Abstract
We use the myotendinous junction of Drosophila flight muscles to explore why many integrin associated proteins (IAPs) are needed and how their function is coordinated. These muscles revealed new functions for IAPs not required for viability: Focal Adhesion Kinase (FAK), RSU1, tensin and vinculin. Genetic interactions demonstrated a balance between positive and negative activities, with vinculin and tensin positively regulating adhesion, while FAK inhibits elevation of integrin activity by tensin, and RSU1 keeps PINCH activity in check. The molecular composition of myofibril termini resolves into 4 distinct layers, one of which is built by a mechanotransduction cascade: vinculin facilitates mechanical opening of filamin, which works with the Arp2/3 activator WASH to build an actin-rich layer positioned between integrins and the first sarcomere. Thus, integration of IAP activity is needed to build the complex architecture of the myotendinous junction, linking the membrane anchor to the sarcomere.
Highlights
Cell adhesion to the extracellular matrix (ECM) is essential for the development and homeostasis of multiple cell types and tissues (Winograd-Katz et al, 2014)
Vinculin recruitment by stretched talin is a paradigm for mechanotransduction, yet we find that vinculin, once opened, can function independently of talin, building an actin zone by promoting mechanical opening of filamin
To understand how integrin-associated proteins (IAPs) contribute to integrin-mediated adhesion we sought to identify defects that occur in their absence
Summary
Cell adhesion to the extracellular matrix (ECM) is essential for the development and homeostasis of multiple cell types and tissues (Winograd-Katz et al, 2014). Adhesion to the ECM is primarily mediated by integrins, a/b heterodimeric transmembrane receptors. The medical importance of integrin adhesion is exemplified by the range of human diseases resulting from its loss or misregulation (Winograd-Katz et al, 2014). The extracellular domains of both integrin subunits binds ECM ligands, whereas it is primarily the intracellular domain of the b subunit that recruits intracellular integrin-associated proteins (IAPs). As b subunit cytoplasmic tails lack enzymatic activity and almost all are short (~47 residues) it is the IAPs that mediate integrin signalling and interaction with the actin cytoskeleton (Campbell and Humphries, 2011). We aim to discover why so many proteins are required for the seemingly simple task of linking the ECM to the actin cytoskeleton. Two features of integrin adhesion sites may help explain the complexity of the machinery required: their complex architecture, and their ability to respond to mechanical forces
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