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1 Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and 2 University of Texas M. D. Anderson Cancer Center, Smithville, Texas 78957
The loss of function of
the tumor suppressor gene TSC2 and its protein product
tuberin promotes the development of benign lesions by stimulating cell
growth, although the role of tuberin in regulating cell migration and
metastasis has not been characterized. In addition, the role of
phosphatidylinositol 3-kinase (PI 3-kinase), an important signaling
event regulating cell migration, in modulating tuberin-deficient cell
motility remains unknown. Using a tuberin-deficient rat smooth muscle
cell line, ELT3, we demonstrate that platelet-derived growth factor
(PDGF) stimulates cell migration by 3.2-fold, whereas vascular
endothelial growth factor (VEGF), transforming growth factor (TGF)-
,
and basic fibroblast growth factor (bFGF) increase migration by 2.1-, 2.1-, and 2.6-fold, respectively. Basal and PDGF-induced migration in
tuberin-deficient ELT3, ELT4, and ERC15 cells was not significantly
different from that of tuberin-positive transformed rat kidney
epithelial 2, airway smooth muscle, and pulmonary arterial vascular
smooth muscle cells. Expression of tuberin in tuberin-deficient
ELT3 cells also had little effect on cell migration. In parallel
experiments, the role of PI 3-kinase activation in ELT3 cell migration
was investigated. LY-294002, a PI 3-kinase inhibitor, decreased
PDGF-induced migration in a concentration-dependent manner with an
IC50 of ~5 µM. LY-294002 also abrogated ELT3 cell
migration stimulated by bFGF and TGF- but not by VEGF and phorbol
12-myristate 13-acetate. Furthermore, transient expression of
constitutively active PI 3-kinase (p110*) was sufficient to induce ELT3
cell migration. However, the migration induced by p110* was less than
that induced by growth factors, suggesting other signaling pathways are
also critically important in modulating growth factor-induced cell
migration. These data suggest that PI 3-kinase is required for growth
factor-induced cell migration and loss of tuberin appears to have
little effect on cell migration.
smooth muscle; airway; vascular; vascular endothelial growth factor; pulmonary lymphangioleiomyomatosis (LAM); remodeling
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