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Plasminogen activator inhibitor type-1 inhibits insulin signaling by competing with αvβ3 integrin for vitronectin binding

  1. Roser López-Alemany1,
  2. Juan M. Redondo2,
  3. Yoshikuni Nagamine3,†,
  4. Pura Muñoz-Cánoves1,4,†

Article first published online: 10 SEP 2003

DOI: 10.1046/j.1432-1033.2003.03453.x

Issue

European Journal of Biochemistry

European Journal of Biochemistry

Volume 270, Issue 5, pages 814–821, March 2003

Additional Information

How to Cite

López-Alemany, R., Redondo, J. M., Nagamine, Y. and Muñoz-Cánoves, P. (2003), Plasminogen activator inhibitor type-1 inhibits insulin signaling by competing with αvβ3 integrin for vitronectin binding. European Journal of Biochemistry, 270: 814–821. doi: 10.1046/j.1432-1033.2003.03453.x

Author Information

  1. 1

    Institut de Recerca Oncològica (IRO), Centre d'Oncologia Molecular, L'Hospitalet de Llobregat, Barcelona, Spain;

  2. 2

    C.B.M. Severo Ochoa, C.S.I.C., U.A.M., Facultat de Ciencias, Madrid, Spain;

  3. 3

    Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland;

  4. 4

    Centre de Regulació Genòmica (CRG), Programa de Diferenciació i Cancer, Barcelona, Spain

  1. †

    Both authors contributed equally to this work.

*P. Muñoz-Cánoves, Centre de Regulació Genòmica (CRG), Programa de Diferenciació i Cáncer, Passeig Maritim 37-49, E-08003 Barcelona, Spain. Fax: + 34 93 224 08 99, Tel.: + 34 93 224 09 33, E-mail: pura.munoz@crg.es Y. Nagamine, Friedrich Miescher Institute for Biomedical Research, Maubeleerstrasse 66, CH-4058 Basel, Switzerland. Fax: + 41 61 697 3976, Tel.: + 41 61 697 6669, E-mail: nagamine@fmi.ch

Publication History

  1. Issue published online: 10 SEP 2003
  2. Article first published online: 10 SEP 2003
  3. (Received 24 September 2002, revised 9 December 2002, accepted 7 January 2003)

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Keywords:

  • plasminogen activator inhibitor type-1;
  • vitronectin;
  • insulin;
  • angiogenesis;
  • HUVEC

Functional cooperation between integrins and growth factor receptors has been reported for several systems, one of which is the modulation of insulin signaling by αvβ3 integrin. Plasminogen activator inhibitor type-1 (PAI-1), competes with αvβ3 integrin for vitronectin (VN) binding. Here we report that PAI-1, in a VN-dependent manner, prevents the cooperation of αvβ3 integrin with insulin signaling in NIH3T3 fibroblasts, resulting in a decrease in insulin-induced protein kinase B (PKB) phosphorylation, vascular endothelial growth factor (VEGF) expression and cell migration. Insulin-induced HUVEC migration and angiotube formation was also enhanced in the presence of VN and this enhancement is inhibited by PAI-1. By using specific PAI-1 mutants with either VN binding or plasminogen activator (PA) inhibiting activities ablated, we have shown that the PAI-1-mediated interference with insulin signaling occurs through its direct interaction with VN, and not through its PA neutralizing activity. Moreover, using cells deficient for uPA receptor (uPAR) we have demonstrated that the inhibition of PAI-1 on insulin signaling is independent of uPAR-VN binding. These results constitute the first demonstration of the interaction of PAI-1 with the insulin response.

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