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Published online 11 December 2000. doi:10.1083/jcb.151.6.1305
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© The Rockefeller University Press, 0021-9525/2000//1305 $5.00
The Journal of Cell Biology, Volume 151, Number 6, , 2000 1305-1320

Original Article

Differential Roles for {alpha}Mβ2 Integrin Clustering or Activation in the Control of Apoptosis via Regulation of Akt and ERK Survival Mechanisms



Ben B. Whitlocka, Shyra Gardaib, Valerie Fadokb, Donna Brattonb, and Peter M. Hensonb

a Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206
b Departments of Pathology and Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80262
D505, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206.303-398-1381303-398-1282

whitlockb{at}njc.org

The role of integrins in leukocyte apoptosis is unclear, some studies suggest enhancement, others inhibition. We have found that β2-integrin engagement on neutrophils can either inhibit or enhance apoptosis depending on the activation state of the integrin and the presence of proapoptotic stimuli. Both clustering and activation of {alpha}Mβ2 delays spontaneous, or unstimulated, apoptosis, maintains mitochondrial membrane potential, and prevents cytochrome c release. In contrast, in the presence of proapoptotic stimuli, such as Fas ligation, TNF{alpha}, or UV irradiation, ligation of active {alpha}Mβ2 resulted in enhanced mitochondrial changes and apoptosis. Clustering of inactive integrins did not show this proapoptotic effect and continued to inhibit apoptosis. This discrepancy was attributed to differential signaling in response to integrin clustering versus activation. Clustered, inactive {alpha}Mβ2 was capable of stimulating the kinases ERK and Akt. Activated {alpha}Mβ2 stimulated Akt, but not ERK. When proapoptotic stimuli were combined with either {alpha}Mβ2 clustering or activation, Akt activity was blocked, allowing integrin activation to enhance apoptosis. Clustered, inactive {alpha}Mβ2 continued to inhibit stimulated apoptosis due to maintained ERK activity. Therefore, β2-integrin engagement can both delay and enhance apoptosis in the same cell, suggesting that integrins can play a dual role in the apoptotic progression of leukocytes.

Key Words: apoptosis • beta2 integrin • mitochondria • cytochrome c • neutrophil

© 2000 The Rockefeller University Press

Ben B. Whitlock and Shyra Gardai contributed equally to the completion of this work.

Abbreviations used in this paper: CytC, cytochrome c; ERK, extracellular signal-regulated kinase; fMLP, formyl-methionine-leucine-phenylalanine; MAPK, mitogen-activated protein kinase; PI-3K, phopshatidylinositol-3 kinase; rhICAM-1, recombinant human intracellular adhesion molecule 1; TNF{alpha}, tumor necrosis factor {alpha}.


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