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

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6, 9, 11, 35, 42...9, 28, 42, 44, 51269, 11, 36, 39, 42...7, 9, 15, 22, 24...1, 3, 9, 19, 31...7, 9, 13, 37, 38, 42...6-9, 22, 24...9, 28, 33, 34, 42...5, 9, 12, 16, 23...4, 7, 9, 14, 20...7, 9, 14, 24, 27...6, 9, 18, 25, 28...7, 9, 17, 24, 35...IGF1/2[extracellularregion]IGF:IGFBP-1 Complex[extracellularregion]Activated thrombin(factor IIa)[extracellularregion]IGF:IGFBP-4 Complex[extracellularregion]IGF1/2[extracellularregion]IGF:IGFBP-5:ALSComplex[extracellularregion]IGF:IGFBP-6 Complex[extracellularregion]IGF1/2[extracellularregion]IGF:IGFBP-3:ALSComplex[extracellularregion]IGF1/2[extracellularregion]IGF1/2[extracellularregion]IGF1/2[extracellularregion]Plasmin[extracellularregion]IGF:IGFBP-2 Complex[extracellularregion]IGF1 [extracellularregion]IGFBP3(227-291)PlasminIGF:IGFBP-6 ComplexIGFBP3(127-291)IGFBP3[extracellularregion]IGF2(25-91)[extracellularregion]IGFBP3(28-168)Cathepsin GIGFALS[extracellularregion]Prostate SpecificAntigenCa2+ [extracellularregion]IGFBP5IGFBP6thrombin heavy chain[extracellularregion]IGFBP3(125-233)IGFALSPLG(20-580)[extracellularregion]IGFBP3(291-187)IGF1 [extracellularregion]IGFALSIGFBP4(157-237)IGFBP4[extracellularregion]IGF1/2IGFBP5[extracellularregion]IGF2(25-91)[extracellularregion]CTSGIGF1/2IGF1 [extracellularregion]IGFBP3(125-187)IGF:IGFBP-2 ComplexIGFBP2(40-328)[extracellularregion]IGF:IGFBP-3:ALSComplexIGFBP1[extracellularregion]thrombin light chain[extracellularregion]IGFBP4PAPP-A and PAPP-A2IGF:IGFBP-1 ComplexIGFBP3(234-291)IGFBP5(21-163)IGFBP5(164-272)PAPPA(81-1628)IGF1 [extracellularregion]MMP-1 and MMP-2IGFBP3(28-126)IGFALS[extracellularregion]IGFBP3(28-124)IGFBP3IGFBP3(28-186)Activated thrombin(factor IIa)IGF:IGFBP-5:ALSComplexIGF1 [extracellularregion]IGFBP2(40-328)IGFBP3(188-291)IGFBP3(169-226)IGF2(25-91)[extracellularregion]IGFBP1IGFBP6[extracellularregion]IGF:IGFBP-4 ComplexIGF2(25-91)[extracellularregion]IGF1 [extracellularregion]IGF2(25-91)[extracellularregion]PLG(581-810)[extracellularregion]IGFBP4(22-156)IGF2(25-91)[extracellularregion]2, 21102, 21


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 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.

Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=381426

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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

View all...
NameTypeDatabase referenceComment
Activated thrombin (factor IIa)ComplexREACT_3298 (Reactome)
CTSGProteinP08311 (Uniprot-TrEMBL) After secretion Cathepsin G is extracellular and associated with the plasma membrane.
Ca2+ [extracellular region]MetaboliteCHEBI:29108 (ChEBI)
Cathepsin GProteinREACT_161260 (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.
IGF1 [extracellular region]ProteinP05019 (Uniprot-TrEMBL)
IGF1/2ProteinREACT_17556 (Reactome)
IGF2(25-91)

[extracellular

region]		ProteinP01344 (Uniprot-TrEMBL)
IGF:IGFBP-1 ComplexComplexREACT_18201 (Reactome)
IGF:IGFBP-2 ComplexComplexREACT_17076 (Reactome)
IGF:IGFBP-3:ALS ComplexComplexREACT_17086 (Reactome)
IGF:IGFBP-4 ComplexComplexREACT_15846 (Reactome)
IGF:IGFBP-5:ALS ComplexComplexREACT_15736 (Reactome)
IGF:IGFBP-6 ComplexComplexREACT_16051 (Reactome)
IGFALS

[extracellular

region]		ProteinP35858 (Uniprot-TrEMBL)
IGFALSProteinP35858 (Uniprot-TrEMBL)
IGFBP1

[extracellular

region]		ProteinP08833 (Uniprot-TrEMBL)
IGFBP1ProteinP08833 (Uniprot-TrEMBL)
IGFBP2(40-328)

[extracellular

region]		ProteinP18065 (Uniprot-TrEMBL)
IGFBP2(40-328)ProteinP18065 (Uniprot-TrEMBL)
IGFBP3

[extracellular

region]		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

[extracellular

region]		ProteinP22692 (Uniprot-TrEMBL)
IGFBP4(157-237)ProteinP22692 (Uniprot-TrEMBL)
IGFBP4(22-156)ProteinP22692 (Uniprot-TrEMBL)
IGFBP4ProteinP22692 (Uniprot-TrEMBL)
IGFBP5

[extracellular

region]		ProteinP24593 (Uniprot-TrEMBL)
IGFBP5(164-272)ProteinP24593 (Uniprot-TrEMBL)
IGFBP5(21-163)ProteinP24593 (Uniprot-TrEMBL)
IGFBP5ProteinP24593 (Uniprot-TrEMBL)
IGFBP6

[extracellular

region]		ProteinP24592 (Uniprot-TrEMBL)
IGFBP6ProteinP24592 (Uniprot-TrEMBL)
MMP-1 and MMP-2REACT_15989 (Reactome)
PAPP-A and PAPP-A2REACT_17786 (Reactome)
PAPPA(81-1628)ProteinQ13219 (Uniprot-TrEMBL)
PLG(20-580)

[extracellular

region]		ProteinP00747 (Uniprot-TrEMBL)
PLG(581-810)

[extracellular

region]		ProteinP00747 (Uniprot-TrEMBL)
PlasminComplexREACT_4641 (Reactome)
Prostate Specific AntigenProteinREACT_160701 (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.
thrombin heavy chain

[extracellular

region]		ProteinP00734 (Uniprot-TrEMBL)
thrombin light chain

[extracellular

region]		ProteinP00734 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
Activated thrombin (factor IIa)mim-catalysisREACT_15373 (Reactome)
Cathepsin Gmim-catalysisREACT_15308 (Reactome)
IGF1/2ArrowREACT_15304 (Reactome)
IGF1/2ArrowREACT_15308 (Reactome)
IGF1/2ArrowREACT_15373 (Reactome)
IGF1/2ArrowREACT_15393 (Reactome)
IGF1/2ArrowREACT_15447 (Reactome)
IGF1/2ArrowREACT_15465 (Reactome)
IGF1/2ArrowREACT_15475 (Reactome)
IGF1/2REACT_15321 (Reactome)
IGF1/2REACT_15325 (Reactome)
IGF1/2REACT_15355 (Reactome)
IGF1/2REACT_15417 (Reactome)
IGF1/2REACT_15419 (Reactome)
IGF1/2REACT_15506 (Reactome)
IGF:IGFBP-1 ComplexArrowREACT_15321 (Reactome)
IGF:IGFBP-2 ComplexArrowREACT_15419 (Reactome)
IGF:IGFBP-3:ALS ComplexArrowREACT_15417 (Reactome)
IGF:IGFBP-3:ALS ComplexREACT_15308 (Reactome)
IGF:IGFBP-3:ALS ComplexREACT_15373 (Reactome)
IGF:IGFBP-3:ALS ComplexREACT_15393 (Reactome)
IGF:IGFBP-3:ALS ComplexREACT_15465 (Reactome)
IGF:IGFBP-3:ALS ComplexREACT_15475 (Reactome)
IGF:IGFBP-4 ComplexArrowREACT_15325 (Reactome)
IGF:IGFBP-4 ComplexREACT_15447 (Reactome)
IGF:IGFBP-5:ALS ComplexArrowREACT_15355 (Reactome)
IGF:IGFBP-5:ALS ComplexREACT_15304 (Reactome)
IGF:IGFBP-6 ComplexArrowREACT_15506 (Reactome)
IGFALSArrowREACT_15304 (Reactome)
IGFALSArrowREACT_15308 (Reactome)
IGFALSArrowREACT_15373 (Reactome)
IGFALSArrowREACT_15393 (Reactome)
IGFALSArrowREACT_15465 (Reactome)
IGFALSArrowREACT_15475 (Reactome)
IGFALSREACT_15355 (Reactome)
IGFALSREACT_15417 (Reactome)
IGFBP1REACT_15321 (Reactome)
IGFBP1mim-catalysisREACT_15321 (Reactome)
IGFBP2(40-328)REACT_15419 (Reactome)
IGFBP2(40-328)mim-catalysisREACT_15419 (Reactome)
IGFBP3(125-187)ArrowREACT_15393 (Reactome)
IGFBP3(125-233)ArrowREACT_15373 (Reactome)
IGFBP3(127-291)ArrowREACT_15475 (Reactome)
IGFBP3(169-226)ArrowREACT_15308 (Reactome)
IGFBP3(188-291)ArrowREACT_15393 (Reactome)
IGFBP3(227-291)ArrowREACT_15308 (Reactome)
IGFBP3(234-291)ArrowREACT_15373 (Reactome)
IGFBP3(28-124)ArrowREACT_15373 (Reactome)
IGFBP3(28-124)ArrowREACT_15393 (Reactome)
IGFBP3(28-126)ArrowREACT_15475 (Reactome)
IGFBP3(28-168)ArrowREACT_15308 (Reactome)
IGFBP3(28-186)ArrowREACT_15465 (Reactome)
IGFBP3(291-187)ArrowREACT_15465 (Reactome)
IGFBP3REACT_15417 (Reactome)
IGFBP3mim-catalysisREACT_15417 (Reactome)
IGFBP4(157-237)ArrowREACT_15447 (Reactome)
IGFBP4(22-156)ArrowREACT_15447 (Reactome)
IGFBP4REACT_15325 (Reactome)
IGFBP4mim-catalysisREACT_15325 (Reactome)
IGFBP5(164-272)ArrowREACT_15304 (Reactome)
IGFBP5(21-163)ArrowREACT_15304 (Reactome)
IGFBP5REACT_15355 (Reactome)
IGFBP5mim-catalysisREACT_15355 (Reactome)
IGFBP6REACT_15506 (Reactome)
IGFBP6mim-catalysisREACT_15506 (Reactome)
MMP-1 and MMP-2mim-catalysisREACT_15475 (Reactome)
PAPP-A and PAPP-A2mim-catalysisREACT_15304 (Reactome)
PAPPA(81-1628)mim-catalysisREACT_15447 (Reactome)
Plasminmim-catalysisREACT_15393 (Reactome)
Prostate Specific Antigenmim-catalysisREACT_15465 (Reactome)
REACT_15304 (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.
REACT_15308 (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.
REACT_15321 (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.


REACT_15325 (Reactome) IGFBP 4 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 4.
REACT_15355 (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.


REACT_15373 (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.
REACT_15393 (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.
REACT_15417 (Reactome) IGFBP 3 binds IGF I or IGF II via the conserved N terminus and C terminus of IGFBP 3. IGFBP 3 also binds ALS via the C terminal portion of IGFBP 3. The interaction is dependent on the glycosylation of ALS.
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 stimulates the effects of IGFs.

REACT_15419 (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.


REACT_15447 (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.
REACT_15465 (Reactome) Prostate specific Antigen (PSA) 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.
REACT_15475 (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.
REACT_15506 (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.
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