The Heparin Binding Domain of Insulin-Like Growth Factor Binding Protein (IGFBP)-3 Increases Susceptibility of IGFBP-3 to Proteolysis

Durham, Susan K.; Suwanichkul, Adisak; Hayes, J. D.; Herington, A. C.; Powell, David R.; Campbell, Phil G.

doi:10.1055/s-2007-978722

Cited by 23 publications

(20 citation statements)

References 23 publications

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“…The simultaneous loss of ELISA reactivity to anti-IGFBP-3 sera during this process may reflect enhanced proteolytic degradation in the new conformation. Proteolytic degradation of IGFBP-3 is influenced by the presence of high salt, heparin, and other agents, which suggests a conformation-dependent susceptibility to proteolysis (9). The exquisite specificity of action exhibited by ferrous (versus ferric) ions on IGFBP-3 suggests a possible physiological role for IGFBP-3 in oxidative metabolism.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor-independent Effects Mediated by a C-terminal Metal-binding Domain of Insulin-like Growth Factor Binding Protein-3

Singh

Charkowicz

Mascarenhas

2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor-independent Effects Mediated by a C-terminal Metal-binding Domain of Insulin-like Growth Factor Binding Protein-3

Singh

Charkowicz

Mascarenhas

2004

Journal of Biological Chemistry

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“…-2 antiplasmin complexing with plasmin) or by the association of IGFBP-3 with a distinct inhibitor, or whether IGFBP-3 is conformationally protected from proteolysis is under investigation. It is increasingly evident that IGFBP-3 is able to associate with molecules outside the IGF system (Campbell et al 1998), and this may regulate IGFBP-3 protection from, or susceptibility to, proteolysis (Durham et al 1999). Inhibition of IGFBP-3 proteolysis by 150 kDa column fractions from RASynF and normal adult serum could suggest that there is an inhibitor that is associated with the IGFBP-3 in the 150 kDa complex.…”

Section: Discussionmentioning

confidence: 99%

Alterations in insulin-like growth factor binding protein-3 proteolysis and complex formation in the arthritic joint

Whellams

Maile²,

Fernihough³

et al. 2000

Journal of Endocrinology

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Increased concentrations of insulin-like growth factor (IGF) system components have previously been observed in rheumatoid arthritis (RA) and osteoarthritis (OA); however, disruption of the IGF axis and the implications for the disease process remain largely unaddressed. This study was undertaken to characterise the IGF binding protein (IGFBP)-3 proteolysis and complex formation systems in synovial fluid and to investigate changes in these systems in arthritic disease, and their impact on the availability of IGF. Western blotting or autoradiography of SDS gels was used to visualise IGFBP-3 or its proteolysis. IGF-I and IGFBP-3 concentrations were determined by radioimmunoassays and acid-labile subunit (ALS) was measured by ELISA. A shift in distribution of IGFBP-3 and IGF-I in RA and OA synovial fluids (RASynF, OASynF) and an associated increase in ALS suggested the presence of 150 kDa ternary complexes. IGFBP-3 proteolysis was decreased in RASynF and OASynF, but was apparent in size-fractionated fluid and resembled serum activity. The presence of serum-like inhibitors of IGFBP-3 proteolysis in RASynF was also demonstrated by the ability of this fluid, and 150 kDa fractions from its size fractionation, to inhibit IGFBP-3 proteolysis in the other synovial fluid. A marked disruption in the IGF system was observed, as considerably more IGF-I was retained in ternary complexes. We also classified the IGFBP-3 proteolysis system in synovial fluid and found it to be disturbed in RASynF and OASynF. These changes may be caused by an increased flux of circulatory proteins into synovial fluid, resulting from an inflammation-induced increase in vascular permeability. The net result in RA and OA would be a decrease in IGF availability in arthritic joints, and therefore loss of a potential anabolic stimulus. This disruption to the IGF axis would influence disease progression in RA and OA.

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“…Their data suggest that the accessibility of the C-terminal basic heparin-binding domain of IGFBP-3 is necessary for proteolysis or for binding of an inhibitor. Plasminogen, prekallikrein, or transferrin, all co-purified with IGFBP-3, might be candidates to bind to the C-terminal basic domain (13,16,22) and protect IGFBP-3 from proteolysis. It is not known whether the IGFBP protease binds to the IGF-II affinity matrix through its interaction with IGFBP-3, IGFBP-associating proteins, or inhibitor complexes.…”

Section: Discussionmentioning

confidence: 99%

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

Oesterreicher

Blum

Schmidt

et al. 2005

Journal of Biological Chemistry

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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 IGF⅐IGFBP 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. The insulin-like growth factors (IGF-I and IGF-II)1 are important regulators of growth, differentiation, and survival.Both their mitogenic and metabolic effects are for the most part mediated through binding and activation of the IGF-I receptor (1). The interaction of IGFs with the IGF-I receptor is controlled by a family of six high affinity IGF-binding proteins (IGFBP-1 to IGFBP-6) exhibiting strong sequence homology. The cysteine-rich N-and C-terminal domains are conserved across all IGFBPs, and both domains appear to be involved in IGF binding (2, 3). In the circulation, the majority of the IGFs are sequestered into ternary 150-kDa complexes with either IGFBP-3 or IGFBP-5 and the 85-kDa acid-labile subunit, prolonging the half-life of IGFs, controlling their transcapillary transport to the target tissues, and functioning as a circulating reservoir of IGFs (4 -6). The IGFBPs can also form binary complexes with IGFs. Limited proteolysis of IGFBPs appears to be the major mechanism for the release of IGFs from binary and ternary IGFBP complexes, resulting in the generation of IGFBP fragments with reduced affinities for IGFs (7,8). Several cation-and serine-dependent serum proteases, such as a disintegrin and metalloprotease (ADAM) 12S, matrix metalloprotease-3, ␣-kallikrein, plasmin, thrombin, and the...

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The Heparin Binding Domain of Insulin-Like Growth Factor Binding Protein (IGFBP)-3 Increases Susceptibility of IGFBP-3 to Proteolysis

Cited by 23 publications

References 23 publications

Insulin-like Growth Factor-independent Effects Mediated by a C-terminal Metal-binding Domain of Insulin-like Growth Factor Binding Protein-3

Insulin-like Growth Factor-independent Effects Mediated by a C-terminal Metal-binding Domain of Insulin-like Growth Factor Binding Protein-3

Alterations in insulin-like growth factor binding protein-3 proteolysis and complex formation in the arthritic joint

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

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