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© The Rockefeller University Press, 0021-9525/1999/12/1419/ $5.00
The Journal of Cell Biology, Volume 147, Number 7, December 27, 1999 1419-1430

Original Article

Primary Megakaryocytes Reveal a Role for Transcription Factor NF-E2 in Integrin {alpha}IIbß3 Signaling

Masamichi Shiragaa, Alec Ritchiea, Sallouha Aidoudia, Veronique Barona, David Wilcoxb, Gilbert Whitec, Belen Ybarrondod, George Murphye, Andrew Leavitte, and Sanford Shattila
a Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037
b Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
c Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
d PharMingen, Inc., San Diego, California 92139
e Department of Laboratory Medicine, The University of California at San Francisco, San Francisco, California 94143

Correspondence to: Sanford Shattil, Department of Vascular Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., VB-5, La Jolla, CA 92037. Tel:(858) 784-7148 Fax:(858) 784-7422 E-mail:shattil{at}scripps.edu.

Platelet integrin {alpha}IIbß3 responds to intracellular signals by binding fibrinogen and triggering cytoskeletal reorganization, but the mechanisms of {alpha}IIbß3 signaling remain poorly understood. To better understand this process, we established conditions to study {alpha}IIbß3 signaling in primary murine megakaryocytes. Unlike platelets, these platelet precursors are amenable to genetic manipulation. Cytokine-stimulated bone marrow cultures produced three arbitrary populations of {alpha}IIbß3-expressing cells with increasing size and DNA ploidy: small progenitors, intermediate-size young megakaryocytes, and large mature megakaryocytes. A majority of the large megakaryocytes bound fibrinogen in response to agonists, while almost none of the smaller cells did. Fibrinogen binding to large megakaryocytes was inhibited by Sindbis virus-mediated expression of isolated ß3 integrin cytoplasmic tails. Strikingly, large megakaryocytes from mice deficient in the transcription factor NF-E2 failed to bind fibrinogen in response to agonists, despite normal surface expression of {alpha}IIbß3. Furthermore, while megakaryocytes from wild-type mice spread on immobilized fibrinogen and exhibited filopodia, lamellipodia and Rho-dependent focal adhesions and stress fibers, NF-E2–deficient megakaryocytes adhered poorly. These studies establish that agonist-induced activation of {alpha}IIbß3 is controlled by NF-E2–regulated signaling pathways that mature late in megakaryocyte development and converge at the ß3 cytoplasmic tail. Megakaryocytes provide a physiologically relevant and tractable system for analysis of bidirectional {alpha}IIbß3 signaling.

Key Words: {alpha}IIbß3, integrin, megakaryocyte, NF-E2, signaling


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