Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)

Stable Identifier
R-HSA-381426
Type
Pathway
Species
Homo sapiens
Compartment
Synonyms
Regulation of IGF Activity by IGFBP
General
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The family of Insulin like Growth Factor Binding Proteins (IGFBPs) share 50% amino acid identity with conserved N terminal and C terminal regions responsible for binding Insulin like Growth Factors I and II (IGF I and IGF II). Most circulating IGFs are in complexes with IGFBPs, which are believed to increase the residence of IGFs in the body, modulate availability of IGFs to target receptors for IGFs, reduce insulin like effects of IGFs, and act as signaling molecules independently of IGFs. About 75% of circulating IGFs are in 1500 220 KDa complexes with IGFBP3 and ALS. Such complexes are too large to pass the endothelial barrier. The remaining 20 25% of IGFs are bound to other IGFBPs in 40 50 KDa complexes. IGFs are released from IGF:IGFBP complexes by proteolysis of the IGFBP. IGFs become active after release, however IGFs may also have activity when still bound to some IGFBPs. IGFBP1 is enriched in amniotic fluid and is produced in the liver under control of insulin (insulin suppresses production). IGFBP1 binding stimulates IGF function. It is unknown which if any protease degrades IGFBP1. IGFBP2 is enriched in cerebrospinal fluid; its binding inhibits IGF function. IGFBP2 is not significantly degraded in circulation. IGFB3, which binds most IGF in the body is enriched in follicular fluid and found in many other tissues. IGFBP 3 may be cleaved by plasmin, thrombin, Prostate specific Antigen (PSA, KLK3), Matrix Metalloprotease-1 (MMP1), and Matrix Metalloprotease-2 (MMP2). IGFBP3 also binds extracellular matrix and binding lowers its affinity for IGFs. IGFBP3 binding stimulates the effects of IGFs. IGFBP4 acts to inhibit IGF function and is cleaved by Pregnancy associated Plasma Protein A (PAPPA) to release IGF. IGFBP5 is enriched in bone matrix; its binding stimulates IGF function. IGFBP5 is cleaved by Pregnancy Associated Plasma Protein A2 (PAPPA2), ADAM9, complement C1s from smooth muscle, and thrombin. Only the cleavage site for PAPPA2 is known. IGFBP6 is enriched in cerebrospinal fluid. It is unknown which if any protease degrades IGFBP6.

Literature References
PubMed ID Title Journal Year
12466191 Cellular actions of the insulin-like growth factor binding proteins

Firth, SM, Baxter, RC

Endocr Rev 2002
11751371 Insulin-like growth factor-binding protein 2 in tumorigenesis: protector or promoter?

Hoeflich, A, Reisinger, R, Lahm, H, Kiess, W, Blum, WF, Kolb, HJ, Weber, MM, Wolf, E

Cancer Res 2001
17047378 The role of insulin-like growth factor binding proteins

Holly, J, Perks, C

Neuroendocrinology 2006
12379487 IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms

Mohan, S, Baylink, DJ

J Endocrinol 2002
11606061 Insulin-like growth factor-binding protein-5 inhibits growth and induces differentiation of mouse osteosarcoma cells

Schneider, MR, Zhou, R, Hoeflich, A, Krebs, O, Schmidt, J, Mohan, S, Wolf, E, Lahm, H

Biochem Biophys Res Commun 2001
12904166 IGF-binding protein-4: biochemical characteristics and functional consequences

Zhou, R, Diehl, D, Hoeflich, A, Lahm, H, Wolf, E

J Endocrinol 2003
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