Interleukin 3-dependent survival by the Akt protein kinase

Interleukin 3-dependent survival by the Akt protein kinase

^*Department of Biology, Massachusetts Institute of Technology, 68-380, Cambridge, MA 02139; ^†Division of Signal Transduction, Beth Israel Hospital and Department of Cell Biology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115; and ^§Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University, Montreal, PQ H3A 2B4, Canada

Contributed by David Baltimore

Abstract

Interleukin 3 (IL-3)-dependent survival of hematopoietic cells is known to rely on the activity of multiple signaling pathways, including a pathway leading to activation of phosphoinositide 3-kinase (PI 3-kinase), and protein kinase Akt is a direct target of PI 3-kinase. We find that Akt kinase activity is rapidly induced by the cytokine IL-3, suggesting a role for Akt in PI 3-kinase-dependent signaling in hematopoetic cells. Dominant-negative mutants of Akt specifically block Akt activation by IL-3 and interfere with IL-3-dependent proliferation. Overexpression of Akt or oncogenic v-akt protects 32D cells from apoptosis induced by IL-3 withdrawal. Apoptosis after IL-3 withdrawal is accelerated by expression of dominant-negative mutants of Akt, indicating that a functional Akt signaling pathway is necessary for cell survival mediated by the cytokine IL-3. Thus Akt appears to be an important mediator of anti-apoptotic signaling in this system.

Footnotes

↵ ‡ To whom reprint requests should be addressed. e-mail: zsongyan{at}mit.edu or cxtf{at}musica.mcgill.ca.
ABBREVIATIONS:

IL,

interleukin;

PI 3-kinase,

phosphoinositide 3-kinase;

GM-CSF,

granulocyte/macrophage colony-stimulating factor;

MAPK,

mitogen-activated protein kinase;

PH,

Pleckstrin homology domain;

FCS,

fetal calf serum;

HA,

hemagglutinin