The insulin-like growth factors (IGFs) are fundamental mitogenic and differentiative polypeptides which exert their effects through specific IGF receptors. In the circulation, IGFs are bound to IGF binding proteins (IGFBPs). The predominant IGFP is IGFBP-3, which regulates IGF hormonal action by serving as a transport protein within the extracellular and vascular spaces, extending the half life of IGF, sequestering IGF and inhibiting the interaction of IGF peptides with their receptors. More recently, IGFBP-3 has been shown in our laboratory to act independently of IGF, through a specific IGFBP-3 binding site, thereby potently inhibiting cell replication. An additional complexity of the regulation of IGF by IGFBP-3 is the recent discovery by our group and others of IGFBP-3 protease(s), which have been detected in numerous biological fluids, where they degrade IGFBP-3 into fragments with reduced affinity for IGF. This modifies the interaction between IGFs and IGFBPs, and alters the bioavailability of IGF peptides for receptors, and the subsequent biological activity and function of IGF. Preliminary data have shown a proteolysed IGFBP-3 fragment to inhibit cell growth, independent of its ability to bind IGF. However, the physiological implications of IGFBP-3 proteolysis have not been fully examined. The IGFBP-3 fragments have been neither fully purified nor characterized, nor has the physiological important of these IGFBP-3 forms been critically examined, either as IGF inhibitors, IGF potentiators, or IGF-independent growth regulators. Thus, the central hypothesis of this proposal is: PROTEOLYSIS OF IGFBP-3 MODIFIES ITS BIOLOGICAL ACTIVITY AND HORMONAL ACTION. We propose to: 1) determine the primary protease-dependent cleavage site(s) of IGFBP-3; 2) express IGFBP-3 and IGFBP-3 proteolytic fragments in a Baculovirus expression system; 3) characterize the IGFBP-3 fragments as IGF inhibitors or potentiators and as IGF-independent regulators of cell growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK051513-01A2
Application #
2463005
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
1998-04-01
Project End
2001-02-28
Budget Start
1998-04-01
Budget End
1999-02-28
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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