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PNAS 98 (18): 10284-10289

Copyright © 2001 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / IMMUNOLOGY

Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes

Tracey S. Mahoney*, Andrew S. Weyrich*,{dagger}, Dan A. Dixon*,{ddagger},§, Thomas McIntyre*,{dagger}, Stephen M. Prescott{dagger},{ddagger},§, and Guy A. Zimmerman*,{dagger},¶

*The Eccles Program in Human Molecular Biology and Genetics, {ddagger}The Huntsman Cancer Institute, and Departments of {dagger}Internal Medicine and Experimental Pathology and §Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT 84112

Received for publication April 24, 2001.

Abstract: Engagement of adhesion molecules on monocytes and other myeloid leukocytes, which are effector cells of the innate immune system, not only tethers the leukocytes in place but also transmits outside-in signals that induce functional changes and alter gene expression. We found that a subset of mRNAs that are induced or amplified by adhesion of human monocytes to P-selectin via its surface ligand, P-selectin glycoprotein 1, have characteristics that suggest specialized translational control. One of these codes for urokinase plasminogen activator receptor (UPAR), a critical surface protease receptor and regulator of cell adhesion and migration. Although UPAR transcripts are induced by adhesion, rapid synthesis of the protein uses constitutive mRNA without a requirement for new transcription and is regulated by mammalian target of rapamycin, demonstrating new biologic roles for the signal-dependent translation pathway controlled by this intracellular kinase. The synthesis of UPAR in monocytic cells is also regulated by eukaryotic translation initiation factor 4E, a second key translational checkpoint, and phosphorylation of eukaryotic translation initiation factor 4E is induced by adhesion of monocytes to P-selectin. Translationally controlled display of UPAR by monocytes confers recognition of the matrix protein, vitronectin. Adhesion-dependent signaling from the plasma membrane to translational checkpoints represents a previously unrecognized mechanism for regulating surface phenotype that may be particularly important for myeloid leukocytes and other cells that are specialized for rapid inflammatory and vascular responses.

To whom reprint requests should be addressed. E-mail: guy.zimmerman{at}hmbg.utah.edu.

Edited by Richard O. Hynes, Massachusetts Institute of Technology, Cambridge, MA, and approved June 27, 2001

This paper was submitted directly (Track II) to the PNAS office.

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