, Volume 22, Issue 1, pp 133–144 | Cite as

The calcium-binding type III repeats domain of thrombospondin-2 binds to fibroblast growth factor 2 (FGF2)

  • Marco Rusnati
  • Patrizia Borsotti
  • Elisabetta Moroni
  • Chiara Foglieni
  • Paola Chiodelli
  • Laura Carminati
  • Denise Pinessi
  • Douglas S. Annis
  • Giulia Paiardi
  • Antonella Bugatti
  • Alessandro Gori
  • Renato Longhi
  • Dorina Belotti
  • Deane F. Mosher
  • Giorgio Colombo
  • Giulia TarabolettiEmail author
Original Paper


Thrombospondin (TSP)-1 and TSP-2 share similar structures and functions, including a remarkable antiangiogenic activity. We have previously demonstrated that a mechanism of the antiangiogenic activity of TSP-1 is the interaction of its type III repeats domain with fibroblast growth factor-2 (FGF2), affecting the growth factor bioavailability and angiogenic activity. Since the type III repeats domain is conserved in TSP-2, this study aimed at investigating whether also TSP-2 retained the ability to interact with FGF2. The FGF2 binding properties of TSP-1 and TSP-2 and their recombinant domains were analyzed by solid-phase binding and surface plasmon resonance assays. TSP-2 bound FGF2 with high affinity (Kd = 1.3 nM). TSP-2/FGF2 binding was inhibited by calcium and heparin. The FGF2-binding domain of TSP-2 was located in the type III repeats and the minimal interacting sequence was identified as the GVTDEKD peptide in repeat 3C, corresponding to KIPDDRD, the active sequence of TSP-1. A second putative FGF2 binding sequence was also identified in repeat 11C of both TSPs. Computational docking analysis predicted that both the TSP-2 and TSP-1-derived heptapeptides interacted with FGF2 with comparable binding properties. Accordingly, small molecules based on the TSP-1 active sequence blocked TSP-2/FGF2 interaction. Binding of TSP-2 to FGF2 impaired the growth factor ability to interact with its cellular receptors, since TSP-2-derived fragments prevented the binding of FGF2 to both heparin (used as a structural analog of heparan sulfate proteoglycans) and FGFR-1. These findings identify TSP-2 as a new FGF2 ligand that shares with TSP-1 the same molecular requirements for interaction with the growth factor and a comparable capacity to block FGF2 interaction with proangiogenic receptors. These features likely contribute to TSP-2 antiangiogenic and antineoplastic activity, providing the rationale for future therapeutic applications.


Thrombospondins FGF2 Angiogenesis Matricellular proteins 



Supported by the Italian Association for Cancer Research (AIRC IG16833 to GT), Ministero dell’Istruzione, Università e Ricerca (MIUR, ex 60%) to MR.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

10456_2018_9644_MOESM1_ESM.pdf (2.2 mb)
Supplementary material 1 (PDF 2281 KB)


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Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Marco Rusnati
    • 1
  • Patrizia Borsotti
    • 2
  • Elisabetta Moroni
    • 3
  • Chiara Foglieni
    • 2
    • 7
  • Paola Chiodelli
    • 1
  • Laura Carminati
    • 2
  • Denise Pinessi
    • 2
  • Douglas S. Annis
    • 4
  • Giulia Paiardi
    • 1
  • Antonella Bugatti
    • 1
  • Alessandro Gori
    • 5
  • Renato Longhi
    • 5
  • Dorina Belotti
    • 2
  • Deane F. Mosher
    • 4
  • Giorgio Colombo
    • 5
    • 6
  • Giulia Taraboletti
    • 2
    Email author
  1. 1.Section of Experimental Oncology and Immunology, Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  2. 2.Tumor Angiogenesis Unit, Department of OncologyIstituto di Ricerche Farmacologiche Mario Negri IRCCSBergamoItaly
  3. 3.IRCCS MultiMedicaMilanoItaly
  4. 4.Departments of Biomolecular Chemistry and MedicineUniversity of WisconsinMadisonUSA
  5. 5.Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche (ICRM-CNR)MilanoItaly
  6. 6.Dipartimento di ChimicaUniversità di PaviaPaviaItaly
  7. 7.Laboratory for Biomedical NeurosciencesNeurocenter of Southern SwitzerlandTorricella-TaverneSwitzerland

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