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J. Biol. Chem., Vol. 280, Issue 11, 9994-10000, March 18, 2005

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Interaction of Insulin-like Growth Factor II (IGF-II) with Multiple Plasma Proteins

HIGH AFFINITY BINDING OF PLASMINOGEN TO IGF-II AND IGF-BINDING PROTEIN-3^*

Sandra Oesterreicher, Werner F. Blum¶, Bernhard Schmidt||, Thomas Braulke**, and Bernd Kübler

From the University Hospital Hamburg Eppendorf, Children's Hospital, Department of Biochemistry, Martinistrasse 52, D-20246 Hamburg, Germany, Eli Lilly and Company, D-61350 Bad Homburg, Germany, ^¶University Children's Hospital, D-35392 Giessen, Germany, and ^|| Department of Biochemistry II, University of Göttingen, 37073 Göttingen, Germany

In the circulation, most of the insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), and IGFBP proteases are bound in high molecular mass complexes of 150 kDa. To investigate molecular interactions between proteins involved in IGF·IGFBP complexes, Cohn fraction IV of human plasma was subjected to IGF-II affinity chromatography followed by reversed-phase high pressure liquid chromatography and analysis of bound proteins. Mass spectrometry and Western blotting revealed the presence of IGFBP-3, IGFBP-5, transferrin, plasminogen, prekallikrein, antithrombin III, and the soluble IGF-II/mannose 6-phosphate receptor in the eluate. Furthermore, an IGFBP-3 protease cleaving also IGFBP-2 but not IGFBP-4 was co-purified from the IGF-II column. Inhibitor studies and IGFBP-3 zymography have demonstrated that the 92-kDa IGFBP-3 protease belongs to the class of serine-dependent proteases. IGF-II ligand blotting and surface plasmon resonance spectrometry have been used to identify plasminogen as a novel high affinity IGF-II-binding protein capable of binding to IGFBP-3 with 50-fold higher affinity than transferrin. In combination with transferrin, the overall binding constant of plasminogen/transferrin for IGF-II was reduced 7-fold. Size exclusion chromatography of the IGF-II matrix eluate revealed that transferrin, plasminogen, and the IGFBP-3 protease are present in different high molecular mass complexes of 440 kDa. The present data indicate that IGFs, low and high affinity IGFBPs, several IGFBP-associated proteins, and IGFBP proteases can interact, which may result in the formation of binary, ternary, and higher molecular weight complexes capable of modulating IGF binding properties and the stability of IGFBPs.

Received for publication, October 15, 2004 , and in revised form, January 10, 2005.

^* This work was supported by the Deutsche Forschungsgemeinschaft (GRK 336 to S. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: University of Hamburg, Children's Hospital, Dept. of Biochemistry, Martinistr. 52, 20246 Hamburg, Germany. Tel.: 49-40-42803-4493; Fax: 49-40-42803-8504; E-mail: braulke{at}uke.uni-hamburg.de.

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