Zasp regulates integrin activation.

Integrins are heterodimeric adhesion receptors that link the extracellular matrix (ECM) to the cytoskeleton. Binding of the scaffold protein, talin, to the cytoplasmic tail of ß-integrin causes a conformational change of the extracellular domains of the integrin heterodimer, thus allowing high-affinity binding of ECM ligands. This essential process is called integrin activation. Here we report that the Z-band alternatively spliced PDZ-motif-containing protein (Zasp) cooperates with talin to activate α5ß1 integrins in mammalian tissue culture and αPS2ßPS integrins in Drosophila. Zasp is a PDZ-LIM-domain-containing protein mutated in human cardiomyopathies previously thought to function primarily in assembly and maintenance of the muscle contractile machinery. Notably, Zasp is the first protein shown to co-activate α5ß1 integrins with talin and appears to do so in a manner distinct from known αIIbß3 integrin co-activators.

Muscle type-specific expression of Zasp52 isoforms in Drosophila.

Zasp52 is a member of the PDZ-LIM domain protein family in Drosophila, which comprises Enigma, ENH, ZASP, Alp, CLP36, RIL, and Mystique in vertebrates. Drosophila Zasp52 colocalizes with integrins at myotendinous junctions and with α-actinin at Z-disks, and is required for muscle attachment as well as Z-disk assembly and maintenance. Here we document 13 Zasp52 splice variants giving rise to six different LIM domains. We demonstrate stage- and tissue-specific expression in different muscle types for Zasp52 isoforms encoding different LIM domains. In particular, LIM1b is expressed only in heart muscle and certain somatic muscles, implying muscle-specific functions in Z-disk assembly or maintenance.

Molecular mechanisms of mechanosensing in muscle development.

Mechanical forces are crucial to muscle development and function, but the mechanisms by which forces are sensed and transduced remain elusive. Evidence implicates the sarcolemmal lattice of integrin adhesion and the Z-disk components of the contractile machinery in such processes. These mechanosensory devices report changes in force to other cellular compartments by self-remodeling. Here we explore how their structural and functional properties integrate to regulate muscle development and maintenance. Developmental Dynamics 238:1526-1534, 2009. (c) 2009 Wiley-Liss, Inc.

Zasp is required for the assembly of functional integrin adhesion sites.

The integrin family of heterodimeric transmembrane receptors mediates cell-matrix adhesion. Integrins often localize in highly organized structures, such as focal adhesions in tissue culture and myotendinous junctions in muscles. Our RNA interference screen for genes that prevent integrin-dependent cell spreading identifies Z band alternatively spliced PDZ-motif protein (zasp), encoding the only known Drosophila melanogaster Alp/Enigma PDZ-LIM domain protein. Zasp localizes to integrin adhesion sites and its depletion disrupts integrin adhesion sites. In tissues, Zasp colocalizes with betaPS integrin in myotendinous junctions and with alpha-actinin in muscle Z lines. Zasp also physically interacts with alpha-actinin. Fly larvae lacking Zasp do not form Z lines and fail to recruit alpha-actinin to the Z line. At the myotendinous junction, muscles detach in zasp mutants with the onset of contractility. Finally, Zasp interacts genetically with integrins, showing that it regulates integrin function. Our observations point to an important function for Zasp in the assembly of integrin adhesion sites both in cell culture and in tissues.