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J. Biol. Chem., Vol. 276, Issue 45, 41668-41674, November 9, 2001

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₂-Macroglobulin: a New Component in the Insulin-like Growth Factor/Insulin-like Growth Factor Binding Protein-1 Axis^*

Melissa Westwood^§¶, John D. Aplin, Ilse A. Collinge^**, Andrew Gill^**, Anne White^§, and J. Martin Gibson^**

From the  Endocrine Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom, the ^§ School of Biological Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom, the  Academic Unit of Obstetrics & Gynaecology, University of Manchester, Research Floor, St. Mary's Hospital, Whitworth Park, Manchester M13 0JH, United Kingdom, and the ^** Department of Diabetes & Endocrinology, Hope Hospital, Salford M6 8HD, United Kingdom

Insulin-like growth factors (IGFs) are crucial for many aspects of development, growth, and metabolism yet control of their activity by IGF-binding proteins (IGFBPs) remains controversial. The effect of IGFBP-1 depends on its phosphorylation status; phosphorylated IGFBP-1 inhibits IGF actions whereas the nonphosphorylated isoform is stimulatory. In order to understand this phenomenon, we purified phosphorylated IGFBP-1 from normal human plasma by immunoaffinity chromatography. Unexpectedly, the resulting preparation enhanced IGF-stimulated 3T3-L1 fibroblast proliferation, due to the presence of a co-purified protein of 700 kDa. Matrix-assisted laser desorption ionization-mass spectrometry and Western immunoblotting analysis identified this co-purified protein as ₂-macroglobulin (₂M). Anti-₂M antibodies co-immunoprecipitated IGFBP-1 from human plasma and from ¹²⁵I-IGFBP-1·₂M complexes formed in vitro. The ¹²⁵I-IGFBP-1/₂M association could be inhibited with excess unlabeled IGFBP-1. Surface plasmon resonance analysis indicated that ₂M preferentially associates with the phosphorylated isoform of IGFBP-1 and that when complexed to ₂M, IGFBP-1 can still bind IGF-I. These findings have functional significance since ₂M protects IGFBP-1 from proteolysis and abrogates the inhibitory effect of phosphorylated IGFBP-1 on IGF-I stimulated 3T3-L1 cell proliferation. We conclude that ₂M is a binding protein of IGFBP-1 which modifies IGF-I/IGFBP-1 actions resulting in enhanced IGF effects. In line with its role in regulating the clearance and activity of other growth factors, we predict that ₂M has a novel and important role in controlling the transport and biological activity of IGFs.

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