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Vol. 9, Issue 11, 3179-3193, November 1998
Departments of Pathology and Surgery, Children's Hospital and
Harvard Medical School, Boston, Massachusetts 02115
The extracellular matrix (ECM) plays an essential role in the
regulation of cell proliferation during angiogenesis. Cell adhesion to
ECM is mediated by binding of cell surface integrin receptors, which both activate intracellular signaling cascades and mediate tension-dependent changes in cell shape and cytoskeletal structure. Although the growth control field has focused on early integrin and growth factor signaling events, recent studies suggest that cell
shape may play an equally critical role in control of cell cycle
progression. Studies were carried out to determine when cell
shape exerts its regulatory effects during the cell cycle and to
analyze the molecular basis for shape-dependent growth control. The
shape of human capillary endothelial cells was controlled by culturing
cells on microfabricated substrates containing ECM-coated adhesive
islands with defined shape and size on the micrometer scale or on
plastic dishes coated with defined ECM molecular coating densities.
Cells that were prevented from spreading in medium containing soluble
growth factors exhibited normal activation of the mitogen-activated
kinase (erk1/erk2) growth signaling pathway. However, in contrast to
spread cells, these cells failed to progress through G1 and enter S
phase. This shape-dependent block in cell cycle progression correlated
with a failure to increase cyclin D1 protein levels, down-regulate the
cell cycle inhibitor p27Kip1, and phosphorylate the
retinoblastoma protein in late G1. A similar block in cell cycle
progression was induced before this same shape-sensitive restriction
point by disrupting the actin network using cytochalasin or by
inhibiting cytoskeletal tension generation using an inhibitor of
actomyosin interactions. In contrast, neither modifications of cell
shape, cytoskeletal structure, nor mechanical tension had any effect on
S phase entry when added at later times. These findings demonstrate
that although early growth factor and integrin signaling events
are required for growth, they alone are not sufficient. Subsequent cell cycle progression and, hence, cell proliferation are
controlled by tension-dependent changes in cell shape and cytoskeletal
structure that act by subjugating the molecular machinery that
regulates the G1/S transition.
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