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The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin

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Abstract

DURING wound healing, migrating cells increase expression of both the vitronectin receptor (VNR) integrins1 and plasminogen activators2,3. Here we report that vitronectin significantly enhances the migration of smooth muscle cells (SMCs), and that the specific VNR αvβ3 is required for cell motility. We also show that the αvβ3 attachment site on vitronectin overlaps with the binding site for plasminogen activator inhibitor (PAI)-l, and that the active conformation of PAI-1 blocks SMC migration. This effect requires high-affinity binding to vitronectin, and is not dependent on the ability of PAI-1 to inhibit plasminogen activators. Formation of a complex between PAI-1 and plasminogen activators results in loss of PAI-1 affinity for vitronectin and restores cell migration. These data demonstrate a direct link between plasminogen activators and integrin-mediated cell migration, and show that PAI-1 can control cell–matrix interactions by regulating the accessibility of specific cell-attachment sites. This indicates that the localization of plasminogen activators at sites of focal contact does not initiate a proteolytic cascade leading to generalized matrix destruction, but instead is required to expose cryptic cell-attachment sites necessary for SMC migration.

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Authors and Affiliations

  1. Biochemistry Department, J. H. Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, Maryland, 20855, USA

    Steingrimur Stefansson & Daniel A. Lawrence

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  1. Steingrimur Stefansson
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  2. Daniel A. Lawrence
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Stefansson, S., Lawrence, D. The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin. Nature 383, 441–443 (1996). https://doi.org/10.1038/383441a0

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