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

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3, 4, 30, 47, 56...12, 22, 26, 30, 47...7, 9, 14, 21, 28...1-3, 30, 41...3, 17, 21, 30, 38...4, 13, 20, 25, 30...4, 21, 28, 30, 35...11, 30, 31, 47, 59...6130, 33, 47, 59, 62276, 10, 15, 21, 26...16, 19, 30, 33, 40...17, 21, 28, 30, 38...5, 6, 8, 10, 15...IGF2(25-91) IGFBP3(28-124)p-MGAT4A APOA2 FN1 CSF1 p-SERPINC1 p-PROC AMBN IGF1,2FGF23 Ca2+ MATN3 p-IL6 PLG(581-810) QSOX1 FAM20C:Phosphorylated FAM20C substratesIGF:IGFBP3:ALSAMELX p-ALB SCG3 KTN1 p-PENK FAM20C MEPE ADAM10 IGFBP3(234-291)IGFBP5IGFALS CHRDL1 IGFBP3p-MEPE p-GOLM1 p-CHRDL1 IGF:IGFBP1p-AMTN AHSG p-BMP4 p-HSP90B1 CTSG AFP p-PNPLA2 SPP1 ATPIGF:IGFBP2IGFBP5(21-163)p-MIA3 MMP2(110-660) SHISA5 p-SERPINA10 p-C4A APP p-CHGB activated thrombin(factor IIa)p-SPARCL1 p-CDH2 PROC IGFBP4 p-APP IGFALS p-ADAM10 APOL1 IGFBP4(22-156)p-MBTPS1 IGF:IGFBP6CST3 p-CSF1 IGF2(25-91) p-CP p-FSTL3 LAMB2 p-VGF SERPIND1 NOTUM p-HRC p-STC2 p-FUCA2 NUCB1 p-SCG3 MMP1(100-469) p-AMBN p-EVA1A IGF1 IGF2(25-91) p-FN1 IGFALSIGF1 IGFBP3(188-291)DNAJC3 SCG2 IGFBP5(164-272)p-IGFBP3 p-MFGE8 p-SERPINA1 p-SDC2 p-APOA5 p-APOB(28-4563) PRKCSH IGF1 IGF1 p-AHSG p-APOA1 p-APOE p-KTN1 IGF1 p-MSLN SPARCL1 p-TGOLN2 p-PCSK9 p-APOA2 PENK p-CYR61 p-APOL1 IGFALSSERPINC1 p-RCN1 PNPLA2 FBN1 PAPPA2 CALU WFS1 p-LTBP1 ITIH2 CP GOLM1 IGF1 IGFBP6 FSTL3 IGFBP6KLK1 IGFBP4 p-DMP1 p-ENAM thrombin light chain PRSS23 CKAP4 IGFBP5 p-WFS1 MEN1 GPC3 IGFBP3(169-226)Factor V precursor FUCA2 p-BPIFB2 IGFBP1 IGFBP3 IGFBP3(227-291)STC2 p-IGFBP7 p-VWA1 TIMP1 KLK2 FAM20A FAM20C:FAM20CsubstratesPAPPA p-MXRA8 ADPp-Factor V precursor SPP2 Cathepsin GIGFBP3(125-187)p-PRSS23 PLG(20-580) p-QSOX1 p-IGFBP4 CHGB IGFBP3(28-126)IGFBP1p-APLP2 p-TIMP1 p-FBN1 p-FGG SDC2 FGA LAMC1 FAM20C MELTF MSLN IGF2(25-91) p-SPP1 p-ITIH2 p-SCG2 GZMH p-MELTF FSTL1 IGFBP7 CDH2 p-VCAN p-LAMB2 p-IGFBP5 p-SPP2 thrombin heavy chain p-KNG1 p-FGF23 p-CALU IGF2(25-91) FAM20C APOA1 IGF1,2p-FGA C4A p-GAS6 IL6 CYR61 p-PDIA6 p-PRKCSH GAS6 MBTPS1 ALB DMP1 IGF:IGFBP5:ALSVGF IGF2(25-91) HSP90B1 IGFBP3 TF p-LAMC1 IGF2(25-91) EVA1A TNC BMP4 SERPINA10 IGF:IGFBP4p-CKAP4 p-LAMB1 PCSK9 MXRA8 p-SERPIND1 KNG1 APOE p-LGALS1 p-TF AMTN p-BMP15 p-DNAJC3 APOA5 ANO8 APOB(28-4563) BPIFB2 MIA3 KLK13 KLK3 p-NOTUM IGFBP2 LAMB1 IGFBP3(127-291)p-GPC3 FAM20C:FAM20AIGFBP3(28-186)p-AFP TGOLN2 p-CST3 PAPPA,PAPPA2VCAN IGF1 MFGE8 p-MEN1 ENAM LGALS1 p-FSTL1 IGF1 p-AMELX p-TNC Prostate SpecificAntigenIGFBP4(157-237)SERPINA1 FGG p-C3 P4HB APLP2 IGFBP3(125-233)LTBP1 IGFBP3(28-168)p-IGFBP1 MMP1,2p-TMEM132A HRC BMP15 p-MATN3 p-ANO8 IGFBP5 MGAT4A VWA1 p-P4HB IGFBP4IGF2(25-91) PDIA6 Plasminp-SHISA5 C3 p-NUCB1 IGFBP2RCN1 IGFBP1 IGFBP3(291-187)TMEM132A 4532, 443632, 44


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.

View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 381426
Reactome-version 
Reactome version: 66

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Bibliography

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History

View all...
CompareRevisionActionTimeUserComment
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
ADAM10 ProteinO14672 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AFP ProteinP02771 (Uniprot-TrEMBL)
AHSG ProteinP02765 (Uniprot-TrEMBL)
ALB ProteinP02768 (Uniprot-TrEMBL)
AMBN ProteinQ9NP70 (Uniprot-TrEMBL)
AMELX ProteinQ99217 (Uniprot-TrEMBL)
AMTN ProteinQ6UX39 (Uniprot-TrEMBL)
ANO8 ProteinQ9HCE9 (Uniprot-TrEMBL)
APLP2 ProteinQ06481 (Uniprot-TrEMBL)
APOA1 ProteinP02647 (Uniprot-TrEMBL)
APOA2 ProteinP02652 (Uniprot-TrEMBL)
APOA5 ProteinQ6Q788 (Uniprot-TrEMBL)
APOB(28-4563) ProteinP04114 (Uniprot-TrEMBL)
APOE ProteinP02649 (Uniprot-TrEMBL)
APOL1 ProteinO14791 (Uniprot-TrEMBL)
APP ProteinP05067 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BMP15 ProteinO95972 (Uniprot-TrEMBL)
BMP4 ProteinP12644 (Uniprot-TrEMBL)
BPIFB2 ProteinQ8N4F0 (Uniprot-TrEMBL)
C3 ProteinP01024 (Uniprot-TrEMBL)
C4A ProteinP0C0L4 (Uniprot-TrEMBL)
CALU ProteinO43852 (Uniprot-TrEMBL)
CDH2 ProteinP19022 (Uniprot-TrEMBL)
CHGB ProteinP05060 (Uniprot-TrEMBL)
CHRDL1 ProteinQ9BU40 (Uniprot-TrEMBL)
CKAP4 ProteinQ07065 (Uniprot-TrEMBL)
CP ProteinP00450 (Uniprot-TrEMBL)
CSF1 ProteinP09603 (Uniprot-TrEMBL)
CST3 ProteinP01034 (Uniprot-TrEMBL)
CTSG ProteinP08311 (Uniprot-TrEMBL) After secretion Cathepsin G is extracellular and associated with the plasma membrane.
CYR61 ProteinO00622 (Uniprot-TrEMBL)
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.
DMP1 ProteinQ13316 (Uniprot-TrEMBL)
DNAJC3 ProteinQ13217 (Uniprot-TrEMBL)
ENAM ProteinQ9NRM1 (Uniprot-TrEMBL)
EVA1A ProteinQ9H8M9 (Uniprot-TrEMBL)
FAM20A ProteinQ96MK3 (Uniprot-TrEMBL)
FAM20C ProteinQ8IXL6 (Uniprot-TrEMBL)
FAM20C:FAM20AComplexR-HSA-8957338 (Reactome)
FAM20C:FAM20C substratesComplexR-HSA-8952321 (Reactome)
FAM20C:Phosphorylated FAM20C substratesComplexR-HSA-8952335 (Reactome)
FBN1 ProteinP35555 (Uniprot-TrEMBL)
FGA ProteinP02671 (Uniprot-TrEMBL)
FGF23 ProteinQ9GZV9 (Uniprot-TrEMBL)
FGG ProteinP02679 (Uniprot-TrEMBL)
FN1 ProteinP02751 (Uniprot-TrEMBL)
FSTL1 ProteinQ12841 (Uniprot-TrEMBL)
FSTL3 ProteinO95633 (Uniprot-TrEMBL)
FUCA2 ProteinQ9BTY2 (Uniprot-TrEMBL)
Factor V precursor ProteinP12259 (Uniprot-TrEMBL)
GAS6 ProteinQ14393 (Uniprot-TrEMBL)
GOLM1 ProteinQ8NBJ4 (Uniprot-TrEMBL)
GPC3 ProteinP51654 (Uniprot-TrEMBL)
GZMH ProteinP20718 (Uniprot-TrEMBL)
HRC ProteinP23327 (Uniprot-TrEMBL)
HSP90B1 ProteinP14625 (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)
IGFBP7 ProteinQ16270 (Uniprot-TrEMBL)
IL6 ProteinP05231 (Uniprot-TrEMBL)
ITIH2 ProteinP19823 (Uniprot-TrEMBL)
KLK1 ProteinP06870 (Uniprot-TrEMBL)
KLK13 ProteinQ9UKR3 (Uniprot-TrEMBL)
KLK2 ProteinP20151 (Uniprot-TrEMBL)
KLK3 ProteinP07288 (Uniprot-TrEMBL)
KNG1 ProteinP01042 (Uniprot-TrEMBL)
KTN1 ProteinQ86UP2 (Uniprot-TrEMBL)
LAMB1 ProteinP07942 (Uniprot-TrEMBL)
LAMB2 ProteinP55268 (Uniprot-TrEMBL)
LAMC1 ProteinP11047 (Uniprot-TrEMBL)
LGALS1 ProteinP09382 (Uniprot-TrEMBL)
LTBP1 ProteinQ14766 (Uniprot-TrEMBL)
MATN3 ProteinO15232 (Uniprot-TrEMBL)
MBTPS1 ProteinQ14703 (Uniprot-TrEMBL)
MELTF ProteinP08582 (Uniprot-TrEMBL)
MEN1 ProteinO00255 (Uniprot-TrEMBL)
MEPE ProteinQ9NQ76 (Uniprot-TrEMBL)
MFGE8 ProteinQ08431 (Uniprot-TrEMBL)
MGAT4A ProteinQ9UM21 (Uniprot-TrEMBL)
MIA3 ProteinQ5JRA6 (Uniprot-TrEMBL)
MMP1(100-469) ProteinP03956 (Uniprot-TrEMBL)
MMP1,2ComplexR-HSA-381470 (Reactome)
MMP2(110-660) ProteinP08253 (Uniprot-TrEMBL)
MSLN ProteinQ13421 (Uniprot-TrEMBL)
MXRA8 ProteinQ9BRK3 (Uniprot-TrEMBL)
NOTUM ProteinQ6P988 (Uniprot-TrEMBL)
NUCB1 ProteinQ02818 (Uniprot-TrEMBL)
P4HB ProteinP07237 (Uniprot-TrEMBL)
PAPPA ProteinQ13219 (Uniprot-TrEMBL)
PAPPA,PAPPA2ComplexR-HSA-381483 (Reactome)
PAPPA2 ProteinQ9BXP8 (Uniprot-TrEMBL)
PCSK9 ProteinQ8NBP7 (Uniprot-TrEMBL)
PDIA6 ProteinQ15084 (Uniprot-TrEMBL)
PENK ProteinP01210 (Uniprot-TrEMBL)
PLG(20-580) ProteinP00747 (Uniprot-TrEMBL)
PLG(581-810) ProteinP00747 (Uniprot-TrEMBL)
PNPLA2 ProteinQ96AD5 (Uniprot-TrEMBL)
PRKCSH ProteinP14314 (Uniprot-TrEMBL)
PROC ProteinP04070 (Uniprot-TrEMBL)
PRSS23 ProteinO95084 (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.
QSOX1 ProteinO00391 (Uniprot-TrEMBL)
RCN1 ProteinQ15293 (Uniprot-TrEMBL)
SCG2 ProteinP13521 (Uniprot-TrEMBL)
SCG3 ProteinQ8WXD2 (Uniprot-TrEMBL)
SDC2 ProteinP34741 (Uniprot-TrEMBL)
SERPINA1 ProteinP01009 (Uniprot-TrEMBL)
SERPINA10 ProteinQ9UK55 (Uniprot-TrEMBL)
SERPINC1 ProteinP01008 (Uniprot-TrEMBL)
SERPIND1 ProteinP05546 (Uniprot-TrEMBL)
SHISA5 ProteinQ8N114 (Uniprot-TrEMBL)
SPARCL1 ProteinQ14515 (Uniprot-TrEMBL)
SPP1 ProteinP10451 (Uniprot-TrEMBL)
SPP2 ProteinQ13103 (Uniprot-TrEMBL)
STC2 ProteinO76061 (Uniprot-TrEMBL)
TF ProteinP02787 (Uniprot-TrEMBL)
TGOLN2 ProteinO43493 (Uniprot-TrEMBL)
TIMP1 ProteinP01033 (Uniprot-TrEMBL)
TMEM132A ProteinQ24JP5 (Uniprot-TrEMBL)
TNC ProteinP24821 (Uniprot-TrEMBL)
VCAN ProteinP13611 (Uniprot-TrEMBL)
VGF ProteinO15240 (Uniprot-TrEMBL)
VWA1 ProteinQ6PCB0 (Uniprot-TrEMBL)
WFS1 ProteinO76024 (Uniprot-TrEMBL)
activated thrombin (factor IIa)ComplexR-HSA-156786 (Reactome)
p-ADAM10 ProteinO14672 (Uniprot-TrEMBL)
p-AFP ProteinP02771 (Uniprot-TrEMBL)
p-AHSG ProteinP02765 (Uniprot-TrEMBL)
p-ALB ProteinP02768 (Uniprot-TrEMBL)
p-AMBN ProteinQ9NP70 (Uniprot-TrEMBL)
p-AMELX ProteinQ99217 (Uniprot-TrEMBL)
p-AMTN ProteinQ6UX39 (Uniprot-TrEMBL)
p-ANO8 ProteinQ9HCE9 (Uniprot-TrEMBL)
p-APLP2 ProteinQ06481 (Uniprot-TrEMBL)
p-APOA1 ProteinP02647 (Uniprot-TrEMBL)
p-APOA2 ProteinP02652 (Uniprot-TrEMBL)
p-APOA5 ProteinQ6Q788 (Uniprot-TrEMBL)
p-APOB(28-4563) ProteinP04114 (Uniprot-TrEMBL)
p-APOE ProteinP02649 (Uniprot-TrEMBL)
p-APOL1 ProteinO14791 (Uniprot-TrEMBL)
p-APP ProteinP05067 (Uniprot-TrEMBL)
p-BMP15 ProteinO95972 (Uniprot-TrEMBL)
p-BMP4 ProteinP12644 (Uniprot-TrEMBL)
p-BPIFB2 ProteinQ8N4F0 (Uniprot-TrEMBL)
p-C3 ProteinP01024 (Uniprot-TrEMBL)
p-C4A ProteinP0C0L4 (Uniprot-TrEMBL)
p-CALU ProteinO43852 (Uniprot-TrEMBL)
p-CDH2 ProteinP19022 (Uniprot-TrEMBL)
p-CHGB ProteinP05060 (Uniprot-TrEMBL)
p-CHRDL1 ProteinQ9BU40 (Uniprot-TrEMBL)
p-CKAP4 ProteinQ07065 (Uniprot-TrEMBL)
p-CP ProteinP00450 (Uniprot-TrEMBL)
p-CSF1 ProteinP09603 (Uniprot-TrEMBL)
p-CST3 ProteinP01034 (Uniprot-TrEMBL)
p-CYR61 ProteinO00622 (Uniprot-TrEMBL)
p-DMP1 ProteinQ13316 (Uniprot-TrEMBL)
p-DNAJC3 ProteinQ13217 (Uniprot-TrEMBL)
p-ENAM ProteinQ9NRM1 (Uniprot-TrEMBL)
p-EVA1A ProteinQ9H8M9 (Uniprot-TrEMBL)
p-FBN1 ProteinP35555 (Uniprot-TrEMBL)
p-FGA ProteinP02671 (Uniprot-TrEMBL)
p-FGF23 ProteinQ9GZV9 (Uniprot-TrEMBL)
p-FGG ProteinP02679 (Uniprot-TrEMBL)
p-FN1 ProteinP02751 (Uniprot-TrEMBL)
p-FSTL1 ProteinQ12841 (Uniprot-TrEMBL)
p-FSTL3 ProteinO95633 (Uniprot-TrEMBL)
p-FUCA2 ProteinQ9BTY2 (Uniprot-TrEMBL)
p-Factor V precursor ProteinP12259 (Uniprot-TrEMBL)
p-GAS6 ProteinQ14393 (Uniprot-TrEMBL)
p-GOLM1 ProteinQ8NBJ4 (Uniprot-TrEMBL)
p-GPC3 ProteinP51654 (Uniprot-TrEMBL)
p-HRC ProteinP23327 (Uniprot-TrEMBL)
p-HSP90B1 ProteinP14625 (Uniprot-TrEMBL)
p-IGFBP1 ProteinP08833 (Uniprot-TrEMBL)
p-IGFBP3 ProteinP17936 (Uniprot-TrEMBL)
p-IGFBP4 ProteinP22692 (Uniprot-TrEMBL)
p-IGFBP5 ProteinP24593 (Uniprot-TrEMBL)
p-IGFBP7 ProteinQ16270 (Uniprot-TrEMBL)
p-IL6 ProteinP05231 (Uniprot-TrEMBL)
p-ITIH2 ProteinP19823 (Uniprot-TrEMBL)
p-KNG1 ProteinP01042 (Uniprot-TrEMBL)
p-KTN1 ProteinQ86UP2 (Uniprot-TrEMBL)
p-LAMB1 ProteinP07942 (Uniprot-TrEMBL)
p-LAMB2 ProteinP55268 (Uniprot-TrEMBL)
p-LAMC1 ProteinP11047 (Uniprot-TrEMBL)
p-LGALS1 ProteinP09382 (Uniprot-TrEMBL)
p-LTBP1 ProteinQ14766 (Uniprot-TrEMBL)
p-MATN3 ProteinO15232 (Uniprot-TrEMBL)
p-MBTPS1 ProteinQ14703 (Uniprot-TrEMBL)
p-MELTF ProteinP08582 (Uniprot-TrEMBL)
p-MEN1 ProteinO00255 (Uniprot-TrEMBL)
p-MEPE ProteinQ9NQ76 (Uniprot-TrEMBL)
p-MFGE8 ProteinQ08431 (Uniprot-TrEMBL)
p-MGAT4A ProteinQ9UM21 (Uniprot-TrEMBL)
p-MIA3 ProteinQ5JRA6 (Uniprot-TrEMBL)
p-MSLN ProteinQ13421 (Uniprot-TrEMBL)
p-MXRA8 ProteinQ9BRK3 (Uniprot-TrEMBL)
p-NOTUM ProteinQ6P988 (Uniprot-TrEMBL)
p-NUCB1 ProteinQ02818 (Uniprot-TrEMBL)
p-P4HB ProteinP07237 (Uniprot-TrEMBL)
p-PCSK9 ProteinQ8NBP7 (Uniprot-TrEMBL)
p-PDIA6 ProteinQ15084 (Uniprot-TrEMBL)
p-PENK ProteinP01210 (Uniprot-TrEMBL)
p-PNPLA2 ProteinQ96AD5 (Uniprot-TrEMBL)
p-PRKCSH ProteinP14314 (Uniprot-TrEMBL)
p-PROC ProteinP04070 (Uniprot-TrEMBL)
p-PRSS23 ProteinO95084 (Uniprot-TrEMBL)
p-QSOX1 ProteinO00391 (Uniprot-TrEMBL)
p-RCN1 ProteinQ15293 (Uniprot-TrEMBL)
p-SCG2 ProteinP13521 (Uniprot-TrEMBL)
p-SCG3 ProteinQ8WXD2 (Uniprot-TrEMBL)
p-SDC2 ProteinP34741 (Uniprot-TrEMBL)
p-SERPINA1 ProteinP01009 (Uniprot-TrEMBL)
p-SERPINA10 ProteinQ9UK55 (Uniprot-TrEMBL)
p-SERPINC1 ProteinP01008 (Uniprot-TrEMBL)
p-SERPIND1 ProteinP05546 (Uniprot-TrEMBL)
p-SHISA5 ProteinQ8N114 (Uniprot-TrEMBL)
p-SPARCL1 ProteinQ14515 (Uniprot-TrEMBL)
p-SPP1 ProteinP10451 (Uniprot-TrEMBL)
p-SPP2 ProteinQ13103 (Uniprot-TrEMBL)
p-STC2 ProteinO76061 (Uniprot-TrEMBL)
p-TF ProteinP02787 (Uniprot-TrEMBL)
p-TGOLN2 ProteinO43493 (Uniprot-TrEMBL)
p-TIMP1 ProteinP01033 (Uniprot-TrEMBL)
p-TMEM132A ProteinQ24JP5 (Uniprot-TrEMBL)
p-TNC ProteinP24821 (Uniprot-TrEMBL)
p-VCAN ProteinP13611 (Uniprot-TrEMBL)
p-VGF ProteinO15240 (Uniprot-TrEMBL)
p-VWA1 ProteinQ6PCB0 (Uniprot-TrEMBL)
p-WFS1 ProteinO76024 (Uniprot-TrEMBL)
thrombin heavy chain ProteinP00734 (Uniprot-TrEMBL)
thrombin light chain ProteinP00734 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-8952289 (Reactome)
ATPR-HSA-8952289 (Reactome)
Cathepsin Gmim-catalysisR-HSA-381500 (Reactome)
FAM20C:FAM20AArrowR-HSA-8952289 (Reactome)
FAM20C:FAM20C substratesR-HSA-8952289 (Reactome)
FAM20C:FAM20C substratesmim-catalysisR-HSA-8952289 (Reactome)
FAM20C:Phosphorylated FAM20C substratesArrowR-HSA-8952289 (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)
IGFBP2R-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)
IGFBP4(157-237)ArrowR-HSA-381518 (Reactome)
IGFBP4(22-156)ArrowR-HSA-381518 (Reactome)
IGFBP4R-HSA-381543 (Reactome)
IGFBP5(164-272)ArrowR-HSA-381537 (Reactome)
IGFBP5(21-163)ArrowR-HSA-381537 (Reactome)
IGFBP5R-HSA-381545 (Reactome)
IGFBP6R-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.


R-HSA-8952289 (Reactome) Extracellular serine/threonine protein kinase FAM20C is an extracellular kinase that can phosphorylate a broad range of secreted protein. FAM20C is bound and allosterically activated by the pseudokinase FAM20A (Tagliabracchi et al. 2012, 2015, Cui et al. 2015).
Loss of function mutations in Fam20C cause Raine Syndrome, an osteosclerotic bone dysplasia (Faundes et al. 2014).
activated thrombin (factor IIa)mim-catalysisR-HSA-381446 (Reactome)
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