help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kübler, B.
Right arrow Articles by Braulke, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kübler, B.
Right arrow Articles by Braulke, T.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Pregnancy
Endocrinology Vol. 139, No. 4 1556-1563
Copyright © 1998 by The Endocrine Society

ARTICLES

Proteolysis of Insulin-Like Growth Factor Binding Proteins by a Novel 50-Kilodalton Metalloproteinase in Human Pregnancy Serum1

Bernd Kübler, Susan Cowell2, Jürgen Zapf and Thomas Braulke

Institute for Biochemistry II (B.K., T.B.), University of Göttingen, Gosslerstrasse 12d, D-37073 Göttingen, Germany; Strangeways Research Laboratory (S.C.), Worts Causeway, Cambridge CB1 4RN, United Kingdom; and Metabolic Unit (J.Z.), Department of Medicine, University Hospital, CH-8091 Zürich, Switzerland

Address all correspondence and requests for reprints to: Thomas Braulke, Ph.D., Institute for Biochemistry II, University of Göttingen, Gosslerstrasse 12 D, D 37073 Göttingen, Germany. E-mail: braulke{at}ukb2-00.uni-bc.gwdg.de

Insulin-like growth factor binding proteins (IGFBP) proteases have been proposed to be involved in changes of serum IGFBP pattern during pregnancy. IGFBP-4 and -5 are degraded specifically by proteases in pregnancy serum in vitro, whereas IGFBP-3 proteolytic activity was also detected in nonpregnancy serum. To identify and characterize IGFBP proteases, human pregnancy serum was fractionated by size exclusion chromatography revealing IGFBP-4 protease activities in fractions coeluting with proteins of approximately 600-kDa and 50- to 100-kDa molecular mass. In both fractions, a predominant 50-kDa gelatinase was found, suggesting that parts of the gelatinase activity might aggregate or are complexed with other proteins forming a higher molecular complex. Hydroxyapatite chromatography and chromatofocusing of the 50- to 100-kDa serum fraction showed that the IGFBP-4 protease and the 50-kDa gelatinase activity were copurified. When the 50-kDa gelatinase-containing band was excised from the polyacrylamide gel, it exhibited IGFBP-4 proteolytic activity, resulting in the formation of 17- and 10-kDa fragments. [125I] IGFBP substrate zymography combined with fragment blotting showed that the 1,10-phenanthroline-sensitive 50-kDa protease activity purified by chromatofocusing also cleaved IGFBP-3 and -5. Other proteases detected in pregnancy serum fractions with Mr estimates of 79-, 30-, and 22-kDa degraded IGFBP-3 and -5 but not IGFBP-4. [125I] IGFBP-5 substrate zymography revealed that the 30-kDa IGFBP protease was inhibited by serine protease inhibitors. Whereas 1,10-phenanthroline inhibited the IGFBP proteolytic activity in the solution assay, serine protease inhibitors failed to affect proteolysis, indicating the predominant contribution of the metalloproteinase to IGFBP proteolysis. Tissue inhibitors of matrix metalloproteinases-1 and -2 revealed weak or no inhibition of IGFBP-4 and -5 proteolytic activity, whereas a hydroxamic acid-based inhibitor, potentially inhibiting disintegrin metalloproteases, completely prevented the proteolysis of IGFBPs. Whereas no specific immunoreactivity of the 50-kDa protein with antimatrix metalloproteinase-1, -2, -3, -9, or -13 antibodies was observed, antidisintegrin domain-specific antibodies bound to the 50-kDa gelatinase.

These studies provide the first direct biochemical evidence that human pregnancy serum contains a 50-kDa IGFBP protease with properties of a soluble disintegrin metalloproteinase that appears to be potentially involved in regulating IGF bioavailability for placental and fetal growth.




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
S. Oesterreicher, W. F. Blum, B. Schmidt, T. Braulke, and B. Kubler
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
J. Biol. Chem., March 18, 2005; 280(11): 9994 - 10000.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
M F Smith, C G Gutierrez, W A Ricke, D G Armstrong, and R Webb
Production of matrix metalloproteinases by cultured bovine theca and granulosa cells
Reproduction, January 1, 2005; 129(1): 75 - 87.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. Wang, J. Grunler, and M. S. Lewitt
Gender-Specific Pattern of Insulin-Like Growth Factor-Binding Protein-3 Protease Activity in Mouse Thyroid
Endocrinology, March 1, 2004; 145(3): 1137 - 1143.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
H. G. Skinner, D. S. Michaud, G. A. Colditz, E. L. Giovannucci, M. J. Stampfer, W. C. Willett, and C. S. Fuchs
Parity, Reproductive Factors, and the Risk of Pancreatic Cancer in Women
Cancer Epidemiol. Biomarkers Prev., May 1, 2003; 12(5): 433 - 438.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
G. M. Rivera and J. E. Fortune
Selection of the Dominant Follicle and Insulin-Like Growth Factor (IGF)-Binding Proteins: Evidence that Pregnancy-Associated Plasma Protein A Contributes to Proteolysis of IGF-Binding Protein 5 in Bovine Follicular Fluid
Endocrinology, February 1, 2003; 144(2): 437 - 446.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. S. Chang, K. Gong, S. Sun, D. Liu, A. K. El-Naggar, F. R. Khuri, W. K. Hong, and H.-Y. Lee
Clinical Significance of Insulin-like Growth Factor-binding Protein-3 Expression in Stage I Non-Small Cell Lung Cancer
Clin. Cancer Res., December 1, 2002; 8(12): 3796 - 3802.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
R. C. Baxter, S. Meka, and S. M. Firth
Molecular Distribution of IGF Binding Protein-5 in Human Serum
J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 271 - 276.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
B. A. Booth, M. Boes, B. L. Dake, K. L. Knudtson, and R. S. Bar
IGFBP-3 binding to endothelial cells inhibits plasmin and thrombin proteolysis
Am J Physiol Endocrinol Metab, January 1, 2002; 282(1): E52 - E58.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
L. Shalamanova, B. Kubler, J.-G. Scharf, and T. Braulke
MDCK cells secrete neutral proteases cleaving insulin-like growth factor-binding protein-2 to -6
Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1221 - E1229.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
D. Byun, S. Mohan, M. Yoo, C. Sexton, D. J. Baylink, and X. Qin
Pregnancy-Associated Plasma Protein-A Accounts for the Insulin-Like Growth Factor (IGF)-Binding Protein-4 (IGFBP-4) Proteolytic Activity in Human Pregnancy Serum and Enhances the Mitogenic Activity of IGF by Degrading IGFBP-4 in Vitro
J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 847 - 854.
[Abstract] [Full Text]

Home page
 Mol Hum ReprodHome page
J.M. Gibson, J.D. Aplin, A. White, and M. Westwood
Regulation of IGF bioavailability in pregnancy
Mol. Hum. Reprod., January 1, 2001; 7(1): 79 - 87.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
H. Yu and T. Rohan
Role of the Insulin-Like Growth Factor Family in Cancer Development and Progression
J Natl Cancer Inst, September 20, 2000; 92(18): 1472 - 1489.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. C. Irwin, L.-F. Suen, B.-H. Cheng, R. Martin, P. Cannon, C. L. Deal, and L. C. Giudice
Human Placental Trophoblasts Secrete a Disintegrin Metalloproteinase Very Similar to the Insulin-Like Growth Factor Binding Protein-3 Protease in Human Pregnancy Serum
Endocrinology, February 1, 2000; 141(2): 666 - 674.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
D. Byun, S. Mohan, C. Kim, K. Suh, M. Yoo, H. Lee, D. J. Baylink, and X. Qin
Studies on Human Pregnancy-Induced Insulin-Like Growth Factor (IGF)-Binding Protein-4 Proteases in Serum: Determination of IGF-II Dependency and Localization of Cleavage Site
J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 373 - 381.
[Abstract] [Full Text]

Home page
 Endocr. Rev.Home page
L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice
The Insulin-Related Ovarian Regulatory System in Health and Disease
Endocr. Rev., August 1, 1999; 20(4): 535 - 582.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
K. Iba, R. Albrechtsen, B. J. Gilpin, F. Loechel, and U. M. Wewer
Cysteine-Rich Domain of Human ADAM 12 (Meltrin {alpha}) Supports Tumor Cell Adhesion
Am. J. Pathol., May 1, 1999; 154(5): 1489 - 1501.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
B. A. Booth, M. Boes, B. L. Dake, and R. S. Bar
Isolation and characterization of plasmin-generated bioactive fragments of IGFBP-3
Am J Physiol Endocrinol Metab, March 1, 1999; 276(3): E450 - E454.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. T. Overgaard, J. Haaning, H. B. Boldt, I. M. Olsen, L. S. Laursen, M. Christiansen, G. J. Gleich, L. Sottrup-Jensen, C. A. Conover, and C. Oxvig
Expression of Recombinant Human Pregnancy-associated Plasma Protein-A and Identification of the Proform of Eosinophil Major Basic Protein as Its Physiological Inhibitor
J. Biol. Chem., September 29, 2000; 275(40): 31128 - 31133.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Z. Shi, W. Xu, F. Loechel, U. M. Wewer, and L. J. Murphy
ADAM 12, a Disintegrin Metalloprotease, Interacts with Insulin-like Growth Factor-binding Protein-3
J. Biol. Chem., June 9, 2000; 275(24): 18574 - 18580.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 1998 by The Endocrine Society