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Related Experiment Videos

Thrombospondin modulates alpha v beta 3 function through integrin-associated protein

A G Gao1, F P Lindberg, J M Dimitry

  • 1Department of Biochemistry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

The Journal of Cell Biology
|October 1, 1996
PubMed
Summary
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Integrin-associated protein (IAP) binds thrombospondin 1 (TS1) and enhances melanoma cell spreading on vitronectin by activating signaling pathways. This interaction involves alpha v beta 3 integrin and Gi protein, impacting cell adhesion and tyrosine phosphorylation.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Integrin Signaling

Background:

  • Integrin-associated protein (IAP) is identified as a receptor for thrombospondin 1's (TS1) cell-binding domain (CBD).
  • IAP interacts with alpha v beta 3 integrin, and antibodies against IAP can impede specific integrin functions.

Purpose of the Study:

  • To investigate the impact of TS1's CBD and a derived peptide (4N1K) on C32 human melanoma cell adhesion and spreading on vitronectin (VN).
  • To elucidate the signaling pathways involved in IAP-mediated cell spreading.

Main Methods:

  • Utilized C32 human melanoma cells expressing IAP, alpha v beta 3, and alpha v beta 5 integrins.
  • Assessed cell adhesion and spreading on varying densities of vitronectin.
  • Examined the effects of TS1, its CBD, 4N1K peptide, and control peptides on cell behavior.

Related Experiment Videos

  • Investigated the role of specific antibodies (LM609, B6H12), signaling inhibitors (calphostin C, wortmannin, tyrosine kinase inhibitors), and pertussis toxin.

    • Main Results:

    • Cell adhesion to low-density VN involves alpha v beta 5, while higher densities engage both alpha v beta 5 and alpha v beta 3, leading to rapid spreading.
    • TS1, CBD, and 4N1K significantly enhanced cell spreading on sparse VN, an effect blocked by anti-alpha v beta 3 and anti-IAP antibodies.
    • Enhanced spreading correlated with increased tyrosine phosphorylation of FAK, paxillin, and a 90 kDa protein.
    • TS1- and 4N1K-induced spreading, along with constitutive spreading on high-density VN, were inhibited by calphostin C, wortmannin, and tyrosine kinase inhibitors.
    • Pertussis toxin selectively blocked TS1-stimulated spreading on low-density VN.

    Conclusions:

    • IAP mediates enhanced melanoma cell spreading on vitronectin through alpha v beta 3 integrin.
    • IAP signaling involves a heterotrimeric Gi protein, acting upstream of PI-3 kinase, PKC, and tyrosine kinases in the cell spreading pathway.
    • These findings reveal a novel signaling mechanism for IAP in regulating cell adhesion and spreading.