PathwayStep4059 PathwayStep4058 PathwayStep4057 PathwayStep4056 PathwayStep4055 PathwayStep4054 PathwayStep4053 PathwayStep4052 PathwayStep4051 PathwayStep4063 PathwayStep4060 PathwayStep4062 PathwayStep4061 Proteolysis of the IGF:IGFBP-5:ALS Complex by PAPP-A2 Proteolysis of the IGF:IGFBP-4 Complex by PAPP-A Proteolysis of the IGF:IGFBP-3:ALS Complex by Thrombin Proteolysis of the IGF:IGFBP-3:ALS Complex by Prostate-specific Antigen Proteolysis of the IGF:IGFBP-3:ALS Complex by Plasmin Proteolysis of the IGF:IGFBP-3:ALS Complex by Cathepsin G Formation of the IGF:IGFBP-6 Complex Proteolysis of the IGF:IGFBP-3:ALS Complex by Matrix Metalloproteinase Formation of the IGF:IGFBP-1 Complex Formation of the IGF:IGFBP-2 Complex Formation of the IGF:IGFBP-3:ALS Complex Formation of the IGF:IGFBP-4 Complex Formation of the IGF:IGFBP-5:ALS Complex Regulation of IGF Activity by IGFBP Edited: May, B, Gopinathrao, G, 2008-11-19 20:02:07 Pubmed11606061 Pubmed11751371 Pubmed12379487 Pubmed12466191 Pubmed12904166 Pubmed17047378 Reactome Database ID Release 43381426 Reactome, http://www.reactome.org ReactomeREACT_15428 Regulation of Insulin-like Growth Factor (IGF) Activity by Insulin-like Growth Factor Binding Proteins (IGFBPs) Reviewed: D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31 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 IGFBP 3 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. IGFBP 1 is enriched in amniotic fluid and is produced in the liver under control of insulin (insulin suppresses production). IGFBP 1 binding stimulates IGF function. It is unknown which if any protease degrades IGFBP 1. IGFBP 2 is enriched in cerebrospinal fluid; its binding inhibits IGF function. IGFBP 2 is not significantly degraded in circulation. IGFBP 3, 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), Matrix Metalloprotease 1, and Matrix Metalloprotease 2. IGFBP 3 also binds extracellular matrix and binding lowers its affinity for IGFs. IGFBP 3 binding stimulates the effects of IGFs. IGFBP 4 acts to inhibit IGF function and is cleaved by Pregnancy associated Plasma Protein A (PAPP A) to release IGF. IGFBP 5 is enriched in bone matrix; its binding stimulates IGF function. IGFBP 5 is cleaved by Pregnancy Associated Plasma Protein A2 (PAPP A2), ADAM 9, complement C1s from smooth muscle, and thrombin. Only the cleavage site for PAPP A2 is known. IGFBP 6 is enriched in cerebrospinal fluid. It is unknown which if any protease degrades IGFBP 6.