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J. Biol. Chem., Vol. 278, Issue 6, 3860-3867, February 7, 2003
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From the Department of Medicine, Baylor College of Medicine,
Houston, Texas 77030
Integrin
Enhanced Activation of Mitogen-activated Protein Kinase and
Myosin Light Chain Kinase by the Pro33 Polymorphism of
Integrin
3*
3 is polymorphic at
residue 33 (Leu33 or Pro33), and the
Pro33 variant exhibits increased outside-in signaling to
focal adhesion kinase and greater actin reorganization. Because focal
adhesion kinase activation and an intact cytoskeleton are critical
links for integrin-mediated signaling to MAPK, we explored the role of
integrin 
IIb3 in this signaling using
Chinese hamster ovary and human kidney 293 cell lines expressing either
the Leu33 or Pro33 isoform of 3.
Compared with Leu33 cells, Pro33 cells
demonstrated substantially greater activation of ERK2 (but not MAPK
family members JNK and p38) upon adhesion to immobilized fibrinogen
(but not fibronectin) and upon integrin cross-linking. ERK2 activation
was mediated through MAPK kinase and required phosphoinositide
3-kinase signaling and an intact actin cytoskeleton. Human
platelets and Chinese hamster ovary cells expressing the Pro33 isoform showed enhanced activation of the ERK2
substrate myosin light chain kinase (MLCK) upon adhering to fibrinogen.
Furthermore, compared with platelets and cells expressing the
Leu33 isoform, the Pro33 variant showed greater
-granule release, clot retraction, and adhesion to fibrinogen under
shear stress, and these functional differences were abolished by MLCK
and MAPK kinase inhibition. Post-integrin occupancy signaling through
MAPK and MLCK after IIb3 cross-linking
may explain in part the increased adhesive properties of the
Pro33 variant of integrin 3.
*
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.
Supported by Grants HL57488 and HL65967 from the National
Institutes of Health and by the Fondren Foundation. To whom
correspondence should be addressed: Thrombosis Research Section, Baylor
College of Medicine, One Baylor Plaza, BCM 286, N1319, Houston, TX
77030. Tel.: 713-798-3480; Fax: 713-798-3415; E-mail:
pbray@bcm.tmc.edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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