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

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

extracellular region

Synonyms

Regulation of IGF Activity by IGFBP

ReviewStatus

5/5

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

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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
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
12466191	Cellular actions of the insulin-like growth factor binding proteins Firth, SM, Baxter, RC	Endocr Rev	2002
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