Letting go: modification of cell adhesion during apoptosis

Suzanne M, Steller H.



Apoptosis, a morphologically and mechanistically distinct form of programmed cell death, is essential for normal animal development and tissue homeostasis. The key executioners in apoptosis are caspases (cysteine aspartases), a family of proteases that have been conserved through much of animal evolution. Caspases are present as inactive precursor proteins in virtually all cells and are specifically activated by proteolytic cleavage. Their activation is regulated by both activators, which promote the conversion of the weakly active precursor caspase to the mature protease, and inhibitors, which prevent unwanted caspase activity and cell death [1]. One important family of caspase inhibitors comprises the inhibitor of apoptosis proteins (IAPs), which can directly bind to and inhibit caspases. In Drosophila, Diap1 is required to prevent inappropriate caspase activation and ubiquitous apoptosis. In response to death-inducing stimuli, antagonists of IAPs such as Reaper, Hid and Grim are produced to inactivate Diap1 and thereby remove the 'brakes on death'. Although caspases are often viewed as general destroyers of cellular components during apoptosis, there are now many studies showing that they can act with a great degree of local specificity to remove unwanted cellular compartments [2-4].

Cleavage by caspases can either activate or inactivate their substrates; for example, cleavage activates the Rho-associated kinase ROCK1, which promotes membrane blebbing [5,6], whereas proteolysis by a caspase inhibits the DNase inhibitor iCAD and unleashes DNA fragmentation by the CAD nuclease [7,8]. Among the very large number of caspase substrates identified so far, only a few have been linked to a specific apoptotic function. In a recent paper in BMC Developmental Biology, Kessler and Muller [9] describe one such example. They show that cleavage of the &豪-catenin homolog Armadillo (Arm) by the effector caspase DrICE in Drosophila is essential to regulate the adhesive properties of apoptotic cells.


Caspase-mediated cleavage of &豪-catenin promotes changes in cell adhesion and cell shape (a) Drosophila; (b) mammals. Adherens junctions are composed of adhesion complexes of E-cadherin (gray bars), &豪-catenin (Armadillo (Arm); green ovals) and &豩-catenin (&豩-cat; blue circles), which link to the actin cytoskeleton. When apoptosis is induced, DrICE in Drosophila or its homolog caspase-3 in mammals are activated in the apoptotic cell (dark gray). DrICE cleaves Armadillo near the amino terminus (Arm&豌N), whereas mammalian capsase-3 cleaves &豪-catenin near both the amino and carboxyl termini. In Drosophila, an early stage of apoptosis has been described in which the cleaved form of Armadillo remains at the membrane linked to &豩-catenin, whereas E-cadherin is removed from the membrane by an unknown mechanism. In mammals, nothing is known so far about an intermediate step in adherens junction degradation in response to induction of apoptosis. At a later stage of apoptosis, all adherens junction components are removed from the membrane and the actin cytoskeleton retracts. Meanwhile, neighboring cells form new adherens junctions with each other and close the gap created by the retraction of the dying cell.

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