Death by unligated integrin
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《细胞学杂志》
Integrins have traditionally beenconsidered relatively indirect inducers of apoptosis, since integrin-mediated adhesion promotes cell survival, whereas inhibiting normal integrin signaling triggers cell death. Now on page 459, Stupack et al. describe an active integrin-mediated death pathway, a finding that helps explain seemingly contradictory earlier results from inhibitor studies and targeted gene disruptions.
The authors studied adherent cells in an artificial three-dimensional extracellular matrix, and found that expression of unligated integrins or integrin ? subunit cytoplasmic domains in these cells induces apoptosis. The cells remained attached to the matrix while initiating cell death, distinguishing this integrin-mediated apoptotic pathway from anoikis, in which cells die after losing adherence. Instead, the unligated integrins recruit caspase 8 to the membrane and activate an apoptotic pathway that is independent of death receptors and distinct from stress-associated apoptosis.
Stupack et al. propose that integrins can act as biosensors, initiating apoptosis when a cell enters a microenvironment that lacks one or more ligands for its integrins. Integrin-mediated death may also explain why specific integrin antagonists cause apoptosis and inhibit angiogenesis, but humans or animals lacking the same integrins exhibit apparently normal angiogenesis. An antagonist that blocks integrin ligation would induce the active integrin-mediated death pathway, whereas disrupting expression of the integrin would only remove one of several possible triggers for apoptosis.(Unligated integrin tails (red) colocaliz)
The authors studied adherent cells in an artificial three-dimensional extracellular matrix, and found that expression of unligated integrins or integrin ? subunit cytoplasmic domains in these cells induces apoptosis. The cells remained attached to the matrix while initiating cell death, distinguishing this integrin-mediated apoptotic pathway from anoikis, in which cells die after losing adherence. Instead, the unligated integrins recruit caspase 8 to the membrane and activate an apoptotic pathway that is independent of death receptors and distinct from stress-associated apoptosis.
Stupack et al. propose that integrins can act as biosensors, initiating apoptosis when a cell enters a microenvironment that lacks one or more ligands for its integrins. Integrin-mediated death may also explain why specific integrin antagonists cause apoptosis and inhibit angiogenesis, but humans or animals lacking the same integrins exhibit apparently normal angiogenesis. An antagonist that blocks integrin ligation would induce the active integrin-mediated death pathway, whereas disrupting expression of the integrin would only remove one of several possible triggers for apoptosis.(Unligated integrin tails (red) colocaliz)