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Proteolysis of Insulin-Like Growth Factor-Binding Protein-3 by Human Skin Keratinocytes in Culture in Comparison to that in Skin Interstitial Fluid: The Role and Regulation of Components of the Plasmin System

Journal of Clinical Endocrinology and Metabolism, ISSN: 0021-972X, Vol: 82, Issue: 6, Page: 1863-1868
1997
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Article Description

Proteolysis of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is an important determinant of IGF action on cells. We have investigated this in a human skin keratinocyte cell line HaCaT. Although these cells did not normally produce an active IGFBP-3 protease, addition of plasminogen resulted in a dose-dependent proteolysis of endogenous and exogenous IGFBP-3, producing fragments similar to those cleaved by skin interstitial fluid, but different from those generated by plasmin. Protease inhibitor profiles suggested the enzyme in the conditioned medium to be a calcium-dependent serine protease. Exogenous IGFBP-3 either inhibited or slightly stimulated IGF-I-induced cell proliferation when it was coincubated or preincubated with the cells, respectively. Both effects were attenuated in the presence of plasminogen. Preincubation of cells with IGF-I or long R IGF-I divergently changed plasminogen activator inhibitor-1 and -2 secretion, but only IGF-I blocked IGFBP-3 proteolysis. Such inhibition was also observed in a cell-free protease assay. IGF-I, however, had no effect on plasmin-induced IGFBP-3 degradation. Together, these data indicate that an IGFBP-3 protease similar to that in skin interstitial fluid is generated in plasminogen-treated HaCaT cells, and it attenuates the effects of IGFBP-3 on IGF action. IGF-I, probably by coupling with IGFBP-3, can protect it from the action of this protease.

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