Regulation of IGF transport and uptake by IGF binding proteins (Homo sapiens)

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8, 17, 18, 39, 57...16, 17, 24, 29, 34...1, 5, 6, 14, 19...12-14, 23, 39...39, 41, 43, 57, 58, 633, 8, 15, 39, 57...7, 11, 18, 25, 38...14, 17, 32, 39, 44...14, 19, 28, 32, 39...420, 39, 41, 57, 582, 14, 18, 19, 32...10, 20, 39, 41, 47...6, 14, 21, 22, 26...IGF2(25-91) thrombin heavy chain IGFBP3 IGFBP4(157-237)IGFBP3(28-126)IGF1 IGF1 IGF1 IGFBP3(28-168)IGFBP4PlasminPLG(20-580) IGFBP3(169-226)IGFBP3(227-291)IGFBP6PAPPA IGFBP5(164-272)KLK2 IGFBP1 IGF1,2IGFALSKLK13 IGFBP3IGFBP4 IGF2(25-91) IGF2(25-91) IGFBP3(28-124)IGFBP6 IGFBP2 CTSGIGFBP1MMP1(100-469) MMP2(110-660) IGFBP5IGFBP5 KLK1 IGFBP2PAPPA2 IGF1,2Ca2+ IGFALS IGFBP5(21-163)IGFBP3(127-291)IGFALSMMP1,2IGFBP3(125-233)IGF:IGFBP3:ALSIGF1 IGF:IGFBP1IGF2(25-91) CTSG KLK3 thrombin light chain IGF:IGFBP5:ALSIGF:IGFBP2IGFBP3(28-186)IGFALS IGF2(25-91) IGF2(25-91) activated thrombin(factor IIa)GZMH Cathepsin GPAPPA,PAPPA2IGF:IGFBP6IGF1 IGFBP4(22-156)IGF2(25-91) IGFBP3(188-291)IGF2(25-91) IGFBP3(291-187)IGFBP3(234-291)IGF1 IGFBP3(125-187)IGF1 IGF1 IGF:IGFBP4PLG(581-810) Prostate SpecificAntigen35, 36309935, 36


Description

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.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
116730view10:28, 11 May 2021EweitzModified title
114814view16:31, 25 January 2021ReactomeTeamReactome version 75
113259view11:32, 2 November 2020ReactomeTeamReactome version 74
112474view15:42, 9 October 2020ReactomeTeamReactome version 73
101385view11:27, 1 November 2018ReactomeTeamreactome version 66
100923view21:03, 31 October 2018ReactomeTeamreactome version 65
100463view19:37, 31 October 2018ReactomeTeamreactome version 64
100009view16:21, 31 October 2018ReactomeTeamreactome version 63
99562view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94031view13:52, 16 August 2017ReactomeTeamreactome version 61
93653view11:29, 9 August 2017ReactomeTeamreactome version 61
88140view12:55, 26 July 2016RyanmillerOntology Term : 'peptide and protein metabolic process' added !
88139view12:55, 26 July 2016RyanmillerOntology Term : 'classic metabolic pathway' added !
86771view09:25, 11 July 2016ReactomeTeamreactome version 56
83284view10:37, 18 November 2015ReactomeTeamVersion54
81777view10:36, 26 August 2015ReactomeTeamVersion53
77094view08:39, 17 July 2014ReactomeTeamFixed remaining interactions
76800view12:18, 16 July 2014ReactomeTeamFixed remaining interactions
76123view10:19, 11 June 2014ReactomeTeamRe-fixing comment source
75835view11:40, 10 June 2014ReactomeTeamReactome 48 Update
75195view09:42, 9 May 2014AnweshaFixing comment source for displaying WikiPathways description
74841view10:06, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
CTSG ProteinP08311 (Uniprot-TrEMBL) After secretion Cathepsin G is extracellular and associated with the plasma membrane.
CTSGProteinP08311 (Uniprot-TrEMBL) After secretion Cathepsin G is extracellular and associated with the plasma membrane.
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Cathepsin GComplexR-HSA-2990877 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
GZMH ProteinP20718 (Uniprot-TrEMBL)
IGF1 ProteinP05019 (Uniprot-TrEMBL)
IGF1,2ComplexR-HSA-381451 (Reactome)
IGF2(25-91) ProteinP01344 (Uniprot-TrEMBL)
IGF:IGFBP1ComplexR-HSA-381539 (Reactome)
IGF:IGFBP2ComplexR-HSA-381473 (Reactome)
IGF:IGFBP3:ALSComplexR-HSA-381536 (Reactome)
IGF:IGFBP4ComplexR-HSA-381509 (Reactome)
IGF:IGFBP5:ALSComplexR-HSA-381423 (Reactome)
IGF:IGFBP6ComplexR-HSA-381482 (Reactome)
IGFALS ProteinP35858 (Uniprot-TrEMBL)
IGFALSProteinP35858 (Uniprot-TrEMBL)
IGFBP1 ProteinP08833 (Uniprot-TrEMBL)
IGFBP1ProteinP08833 (Uniprot-TrEMBL)
IGFBP2 ProteinP18065 (Uniprot-TrEMBL)
IGFBP2ProteinP18065 (Uniprot-TrEMBL)
IGFBP3 ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(125-187)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(125-233)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(127-291)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(169-226)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(188-291)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(227-291)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(234-291)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(28-124)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(28-126)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(28-168)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(28-186)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3(291-187)ProteinP17936 (Uniprot-TrEMBL)
IGFBP3ProteinP17936 (Uniprot-TrEMBL)
IGFBP4 ProteinP22692 (Uniprot-TrEMBL)
IGFBP4(157-237)ProteinP22692 (Uniprot-TrEMBL)
IGFBP4(22-156)ProteinP22692 (Uniprot-TrEMBL)
IGFBP4ProteinP22692 (Uniprot-TrEMBL)
IGFBP5 ProteinP24593 (Uniprot-TrEMBL)
IGFBP5(164-272)ProteinP24593 (Uniprot-TrEMBL)
IGFBP5(21-163)ProteinP24593 (Uniprot-TrEMBL)
IGFBP5ProteinP24593 (Uniprot-TrEMBL)
IGFBP6 ProteinP24592 (Uniprot-TrEMBL)
IGFBP6ProteinP24592 (Uniprot-TrEMBL)
KLK1 ProteinP06870 (Uniprot-TrEMBL)
KLK13 ProteinQ9UKR3 (Uniprot-TrEMBL)
KLK2 ProteinP20151 (Uniprot-TrEMBL)
KLK3 ProteinP07288 (Uniprot-TrEMBL)
MMP1(100-469) ProteinP03956 (Uniprot-TrEMBL)
MMP1,2ComplexR-HSA-381470 (Reactome)
MMP2(110-660) ProteinP08253 (Uniprot-TrEMBL)
PAPPA ProteinQ13219 (Uniprot-TrEMBL)
PAPPA,PAPPA2ComplexR-HSA-381483 (Reactome)
PAPPA2 ProteinQ9BXP8 (Uniprot-TrEMBL)
PLG(20-580) ProteinP00747 (Uniprot-TrEMBL)
PLG(581-810) ProteinP00747 (Uniprot-TrEMBL)
PlasminComplexR-HSA-158770 (Reactome)
Prostate Specific AntigenComplexR-HSA-2990872 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
activated thrombin (factor IIa)ComplexR-HSA-156786 (Reactome)
thrombin heavy chain ProteinP00734 (Uniprot-TrEMBL)
thrombin light chain ProteinP00734 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
Cathepsin Gmim-catalysisR-HSA-381500 (Reactome)
IGF1,2ArrowR-HSA-381435 (Reactome)
IGF1,2ArrowR-HSA-381446 (Reactome)
IGF1,2ArrowR-HSA-381461 (Reactome)
IGF1,2ArrowR-HSA-381466 (Reactome)
IGF1,2ArrowR-HSA-381500 (Reactome)
IGF1,2ArrowR-HSA-381518 (Reactome)
IGF1,2ArrowR-HSA-381537 (Reactome)
IGF1,2R-HSA-381412 (Reactome)
IGF1,2R-HSA-381487 (Reactome)
IGF1,2R-HSA-381496 (Reactome)
IGF1,2R-HSA-381503 (Reactome)
IGF1,2R-HSA-381543 (Reactome)
IGF1,2R-HSA-381545 (Reactome)
IGF:IGFBP1ArrowR-HSA-381487 (Reactome)
IGF:IGFBP2ArrowR-HSA-381412 (Reactome)
IGF:IGFBP3:ALSArrowR-HSA-381496 (Reactome)
IGF:IGFBP3:ALSR-HSA-381435 (Reactome)
IGF:IGFBP3:ALSR-HSA-381446 (Reactome)
IGF:IGFBP3:ALSR-HSA-381461 (Reactome)
IGF:IGFBP3:ALSR-HSA-381466 (Reactome)
IGF:IGFBP3:ALSR-HSA-381500 (Reactome)
IGF:IGFBP4ArrowR-HSA-381543 (Reactome)
IGF:IGFBP4R-HSA-381518 (Reactome)
IGF:IGFBP5:ALSArrowR-HSA-381545 (Reactome)
IGF:IGFBP5:ALSR-HSA-381537 (Reactome)
IGF:IGFBP6ArrowR-HSA-381503 (Reactome)
IGFALSArrowR-HSA-381435 (Reactome)
IGFALSArrowR-HSA-381446 (Reactome)
IGFALSArrowR-HSA-381461 (Reactome)
IGFALSArrowR-HSA-381466 (Reactome)
IGFALSArrowR-HSA-381500 (Reactome)
IGFALSArrowR-HSA-381537 (Reactome)
IGFALSR-HSA-381496 (Reactome)
IGFALSR-HSA-381545 (Reactome)
IGFBP1R-HSA-381487 (Reactome)
IGFBP1mim-catalysisR-HSA-381487 (Reactome)
IGFBP2R-HSA-381412 (Reactome)
IGFBP2mim-catalysisR-HSA-381412 (Reactome)
IGFBP3(125-187)ArrowR-HSA-381461 (Reactome)
IGFBP3(125-233)ArrowR-HSA-381446 (Reactome)
IGFBP3(127-291)ArrowR-HSA-381435 (Reactome)
IGFBP3(169-226)ArrowR-HSA-381500 (Reactome)
IGFBP3(188-291)ArrowR-HSA-381461 (Reactome)
IGFBP3(227-291)ArrowR-HSA-381500 (Reactome)
IGFBP3(234-291)ArrowR-HSA-381446 (Reactome)
IGFBP3(28-124)ArrowR-HSA-381446 (Reactome)
IGFBP3(28-124)ArrowR-HSA-381461 (Reactome)
IGFBP3(28-126)ArrowR-HSA-381435 (Reactome)
IGFBP3(28-168)ArrowR-HSA-381500 (Reactome)
IGFBP3(28-186)ArrowR-HSA-381466 (Reactome)
IGFBP3(291-187)ArrowR-HSA-381466 (Reactome)
IGFBP3R-HSA-381496 (Reactome)
IGFBP3mim-catalysisR-HSA-381496 (Reactome)
IGFBP4(157-237)ArrowR-HSA-381518 (Reactome)
IGFBP4(22-156)ArrowR-HSA-381518 (Reactome)
IGFBP4R-HSA-381543 (Reactome)
IGFBP4mim-catalysisR-HSA-381543 (Reactome)
IGFBP5(164-272)ArrowR-HSA-381537 (Reactome)
IGFBP5(21-163)ArrowR-HSA-381537 (Reactome)
IGFBP5R-HSA-381545 (Reactome)
IGFBP5mim-catalysisR-HSA-381545 (Reactome)
IGFBP6R-HSA-381503 (Reactome)
IGFBP6mim-catalysisR-HSA-381503 (Reactome)
MMP1,2mim-catalysisR-HSA-381435 (Reactome)
PAPPA,PAPPA2mim-catalysisR-HSA-381518 (Reactome)
PAPPA,PAPPA2mim-catalysisR-HSA-381537 (Reactome)
Plasminmim-catalysisR-HSA-381461 (Reactome)
Prostate Specific Antigenmim-catalysisR-HSA-381466 (Reactome)
R-HSA-381412 (Reactome) IGFBP 2 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 2.

IGFBP 2 is enriched in cerebrospinal fluid and inhibits IGF function. IGFBP 2 is not significantly degraded in circulation.


R-HSA-381435 (Reactome) Matrix Metalloprotease-1 and -2 cleave IGFBP-3 in the IGF:IGFBP-3:ALS Complex between amino acids 126 and 127, releasing IGF. The reaction has been demonstrated in vivo.
R-HSA-381446 (Reactome) Thrombin cleaves IGFBP-3 in the IGF:IGFBP-3:ALS Complex between amino acids 124 and 125 and between amino acids 233 and 234, releasing IGF.
R-HSA-381461 (Reactome) Plasmin cleaves IGFBP-3 in the IGF:IGFBP-3:ALS Complex between amino acids 124 and 125 and between amino acids 187 and 188, releasing IGF.
R-HSA-381466 (Reactome) Prostate specific Antigen (PSA, KLK3) cleaves IGFBP-3 in the IGF:IGFBP-3:ALS Complex between amino acids 186 and 187. Other cleavage sites were observed but not reproducibly. These may have been caused by impurities in the PSA preparation.
R-HSA-381487 (Reactome) IGFBP 1 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 1.

IGFBP 1 is enriched in amniotic fluid and is produced in the liver under control of insulin (insulin suppresses production). IGFBP 1 acts to stimulate IGF function. It is unknown which if any protease degrades IGFBP 1.


R-HSA-381496 (Reactome) IGFBP3 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 3. IGFBP3 also binds ALS via the C terminal portion of IGFBP3. The interaction is dependent on the glycosylation of ALS.
IGFBP3, which binds most IGF in the body, is enriched in follicular fluid and found in many other tissues. IGFBP3 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 stimulates the effects of IGFs.

R-HSA-381500 (Reactome) Cathepsin G cleaves IGFBP-3 between amino acids 168 and 169 and between amino acids 226 and 227, releasing IGF from the IGF:IGFBP-3:ALS Complex.
R-HSA-381503 (Reactome) IGFBP-6 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP-6. IGFBP-6 binds IGF II with greater affinity than IGF I.
R-HSA-381518 (Reactome) Pregnancy associated Plasma Protein A (PPAP-A) cleaves IGFBP-4 in the IGF:IGFBP-4 Complex between amino acids 156 and 157, releasing IGF.
R-HSA-381537 (Reactome) Both Pregnancy Associated Plasma Protein A (PAPP-A) and A2 (PAPP-A2) cleave IGFBP-5 in the IGF:IGFBP-5:ALS Complex between amino acids 163 and 164, releasing IGF. PPAP-A has also been shown to cleave IGFBP-5 that is not complexed with IGF.
R-HSA-381543 (Reactome) IGFBP 4 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 4.
R-HSA-381545 (Reactome) IGFBP 5 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 5. IGFBP 5 also binds ALS via the central portion of IGFBP 5. About 55% of IGF:IGFBP 5 complexes contain ALS.

IGFBP 5 is enriched in bone matrix and acts to stimulate 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. About 55% of IGF:IGFBP 5 complexes contain ALS; 45% contain only IGF and IGFBP 5.


activated thrombin (factor IIa)mim-catalysisR-HSA-381446 (Reactome)
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