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J. Biol. Chem., Vol. 277, Issue 27, 24057-24066, July 5, 2002
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From the ¶ Lineberger Comprehensive Cancer Center, Department
of Medicine and Pharmacology, University of North Carolina School of
Medicine, Chapel Hill, North Carolina 27599 and
§ Procter and Gamble Corporation, Cincinnati, Ohio 45202, and Amgen Corporation, Thousand Oaks, California 91320
Mer is a member of the
Axl/Mer/Tyro3 receptor
tyrosine kinase family, a family whose physiological function is not
well defined. We constructed a Mer chimera using the
epidermal growth factor receptor (EGFR) extracellular and transmembrane
domains and the Mer cytoplasmic domain. Stable transfection
of the Mer chimera into interleukin 3 (IL-3)-dependent murine 32D cells resulted in
ligand-activable surface receptor that tyrosine autophosphorylated, stimulated intracellular signaling, and dramatically reduced apoptosis initiated by IL-3 withdrawal. However, unlike multiple other
ectopically expressed receptor tyrosine kinases including full-length
EGFR or an EGFR/Axl chimera, the Mer chimera
did not stimulate proliferation. Moreover, and in contrast to EGFR,
Mer chimera activation induced adherence and cell
flattening in the normally suspension-growing 32D cells. The
Mer chimera signal also blocked IL-3-dependent proliferation leading to G1/S arrest, dephosphorylation of
retinoblastoma protein, and elongation of cellular processes. Unlike
other agonists that lead to a slow (4-8 days)
ligand-dependent differentiation of 32D cells, the combined
Mer and IL-3 signal resulted in differentiated morphology
and growth cessation in the first 24 h. Thus the Mer chimera blocks apoptosis without stimulating growth and produces cytoskeletal alterations; this outcome is clearly separable from the
proliferative signal produced by most receptor tyrosine kinases.
Mer Receptor Tyrosine Kinase Signaling
PREVENTION OF APOPTOSIS AND ALTERATION OF CYTOSKELETAL
ARCHITECTURE WITHOUT STIMULATION OR PROLIFERATION*
,,§,
*
This work was supported by NCI Grants CA-68346 and CA-49240
from the National Institutes of Health (to H. S. E.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
These authors contributed equally to this work.
To whom correspondence should be addressed. Fax: 919-966-3015;
E-mail: hse@med.unc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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