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

From WikiPathways

Revision as of 10:37, 18 November 2015 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
29, 43, 47, 49, 51...11, 30, 43, 47, 49...1, 5, 6, 8, 11...8, 21, 24, 29, 31...6026, 28, 43, 47, 5115, 18, 22, 27, 29...4, 12, 19, 26, 42...23, 26, 28, 38, 43...1, 2, 5, 8, 9, 11...8, 16, 21, 31, 43...8, 10, 16, 31, 41...3, 8, 14, 21, 33...13, 26, 39, 43, 47...IGF1 IGFBP3(28-168)PLG(20-580) IGF:IGFBP6MMP1,2IGFBP3 IGF2(25-91) IGFBP3(169-226)Prostate SpecificAntigenIGFALS Cathepsin GIGFBP5IGFBP6thrombin light chainactivated thrombin(factor IIa)IGFALSPLG(581-810) IGFBP3(234-291)IGF1 IGFBP5(21-163)IGFBP4(157-237)IGFBP4 IGFALSIGFBP5 IGF2(25-91) IGFBP3(28-126)IGF1,2IGF1 IGFBP3(28-124)IGF:IGFBP2IGFBP2 IGF:IGFBP3:ALSIGFBP1 Ca2+ IGFBP4IGFBP3(227-291)IGF:IGFBP1IGFBP3(125-233)IGFBP5(164-272)PAPPA,PAPPA2IGF1,2IGF1 IGFBP3(125-187)IGFBP3(127-291)IGFALS IGFBP3(188-291)IGFBP3IGFBP3(291-187)thrombin heavy chainIGF:IGFBP5:ALSIGF1 IGFBP2PlasminCTSGIGF2(25-91) IGFBP1IGFBP6 IGF:IGFBP4IGF2(25-91) IGF1 IGF2(25-91) IGFBP3(28-186)IGFBP4(22-156)IGF2(25-91) 547, 257, 25


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.

Source:Reactome.

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Collett-Solberg PF, Nunn SE, Gibson TB, Cohen P.; ''Identification of novel high molecular weight insulin-like growth factor-binding protein-3 association proteins in human serum.''; PubMed Europe PMC Scholia
  2. Bach LA, Hsieh S, Brown AL, Rechler MM.; ''Recombinant human insulin-like growth factor (IGF)-binding protein-6 inhibits IGF-II-induced differentiation of L6A1 myoblasts.''; PubMed Europe PMC Scholia
  3. Galanis M, Firth SM, Bond J, Nathanielsz A, Kortt AA, Hudson PJ, Baxter RC.; ''Ligand-binding characteristics of recombinant amino- and carboxyl-terminal fragments of human insulin-like growth factor-binding protein-3.''; PubMed Europe PMC Scholia
  4. Payet LD, Firth SM, Baxter RC.; ''The role of the acid-labile subunit in regulating insulin-like growth factor transport across human umbilical vein endothelial cell monolayers.''; PubMed Europe PMC Scholia
  5. Kuang Z, Yao S, McNeil KA, Thompson JA, Bach LA, Forbes BE, Wallace JC, Norton RS.; ''Cooperativity of the N- and C-terminal domains of insulin-like growth factor (IGF) binding protein 2 in IGF binding.''; PubMed Europe PMC Scholia
  6. Headey SJ, Keizer DW, Yao S, Brasier G, Kantharidis P, Bach LA, Norton RS.; ''C-terminal domain of insulin-like growth factor (IGF) binding protein-6: structure and interaction with IGF-II.''; PubMed Europe PMC Scholia
  7. Butkowski RJ, Elion J, Downing MR, Mann KG.; ''Primary structure of human prethrombin 2 and alpha-thrombin.''; PubMed Europe PMC Scholia
  8. Byun D, Mohan S, Yoo M, Sexton C, Baylink DJ, Qin X.; ''Pregnancy-associated plasma protein-A accounts for the insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) proteolytic activity in human pregnancy serum and enhances the mitogenic activity of IGF by degrading IGFBP-4 in vitro.''; PubMed Europe PMC Scholia
  9. Booth BA, Boes M, Dake BL, Knudtson KL, Bar RS.; ''IGFBP-3 binding to endothelial cells inhibits plasmin and thrombin proteolysis.''; PubMed Europe PMC Scholia
  10. Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ, Hays LG, Yates JR, Conover CA.; ''The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A.''; PubMed Europe PMC Scholia
  11. Zhou R, Diehl D, Hoeflich A, Lahm H, Wolf E.; ''IGF-binding protein-4: biochemical characteristics and functional consequences.''; PubMed Europe PMC Scholia
  12. Headey SJ, Leeding KS, Norton RS, Bach LA.; ''Contributions of the N- and C-terminal domains of IGF binding protein-6 to IGF binding.''; PubMed Europe PMC Scholia
  13. Belgorosky A, Rivarola MA.; ''Insulin-like growth factor binding protein (IGFBP)-3-bound IGF-I and IGFBP-3-bound IGF-II in growth hormone deficiency.''; PubMed Europe PMC Scholia
  14. Bond JJ, Meka S, Baxter RC.; ''Binding characteristics of pro-insulin-like growth factor-II from cancer patients: binary and ternary complex formation with IGF binding proteins-1 to -6.''; PubMed Europe PMC Scholia
  15. Jansson M, Andersson G, Uhlén M, Nilsson B, Kördel J.; ''The insulin-like growth factor (IGF)binding protein 1 binding epitope on IGF-I probed by heteronuclear NMR spectroscopy and mutational analysis.''; PubMed Europe PMC Scholia
  16. Degen SJ, Davie EW.; ''Nucleotide sequence of the gene for human prothrombin.''; PubMed Europe PMC Scholia
  17. Fowlkes JL, Enghild JJ, Suzuki K, Nagase H.; ''Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures.''; PubMed Europe PMC Scholia
  18. Rajah R, Katz L, Nunn S, Solberg P, Beers T, Cohen P.; ''Insulin-like growth factor binding protein (IGFBP) proteases: functional regulators of cell growth.''; PubMed Europe PMC Scholia
  19. Juul A, Dalgaard P, Blum WF, Bang P, Hall K, Michaelsen KF, Müller J, Skakkebaek NE.; ''Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation.''; PubMed Europe PMC Scholia
  20. Janosi JB, Firth SM, Bond JJ, Baxter RC, Delhanty PJ.; ''N-Linked glycosylation and sialylation of the acid-labile subunit. Role in complex formation with insulin-like growth factor (IGF)-binding protein-3 and the IGFs.''; PubMed Europe PMC Scholia
  21. Arai T, Parker A, Busby W, Clemmons DR.; ''Heparin, heparan sulfate, and dermatan sulfate regulate formation of the insulin-like growth factor-I and insulin-like growth factor-binding protein complexes.''; PubMed Europe PMC Scholia
  22. Firth SM, Baxter RC.; ''Cellular actions of the insulin-like growth factor binding proteins.''; PubMed Europe PMC Scholia
  23. Qin X, Byun D, Lau KH, Baylink DJ, Mohan S.; ''Evidence that the interaction between insulin-like growth factor (IGF)-II and IGF binding protein (IGFBP)-4 is essential for the action of the IGF-II-dependent IGFBP-4 protease.''; PubMed Europe PMC Scholia
  24. Laursen LS, Overgaard MT, Nielsen CG, Boldt HB, Hopmann KH, Conover CA, Sottrup-Jensen L, Giudice LC, Oxvig C.; ''Substrate specificity of the metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) assessed by mutagenesis and analysis of synthetic peptides: substrate residues distant from the scissile bond are critical for proteolysis.''; PubMed Europe PMC Scholia
  25. Twigg SM, Baxter RC.; ''Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit.''; PubMed Europe PMC Scholia
  26. Cianfarani S, Frost VJ, Savage MO, Holly JM.; ''Glucose does not influence the insulin-like growth factor (JGF) binding to carrier proteins (IGFBPs): analysis of rat and human serum by western ligand blotting.''; PubMed Europe PMC Scholia
  27. Lalou C, Silve C, Rosato R, Segovia B, Binoux M.; ''Interactions between insulin-like growth factor-I (IGF-I) and the system of plasminogen activators and their inhibitors in the control of IGF-binding protein-3 production and proteolysis in human osteosarcoma cells.''; PubMed Europe PMC Scholia
  28. Binkert C, Landwehr J, Mary JL, Schwander J, Heinrich G.; ''Cloning, sequence analysis and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGFBP-2).''; PubMed Europe PMC Scholia
  29. Hoeflich A, Reisinger R, Lahm H, Kiess W, Blum WF, Kolb HJ, Weber MM, Wolf E.; ''Insulin-like growth factor-binding protein 2 in tumorigenesis: protector or promoter?''; PubMed Europe PMC Scholia
  30. Bach LA, Hsieh S, Sakano K, Fujiwara H, Perdue JF, Rechler MM.; ''Binding of mutants of human insulin-like growth factor II to insulin-like growth factor binding proteins 1-6.''; PubMed Europe PMC Scholia
  31. Angelloz-Nicoud P, Harel L, Binoux M.; ''Recombinant human insulin-like growth factor (IGF) binding protein-3 stimulates prostate carcinoma cell proliferation via an IGF-dependent mechanism. Role of serine proteases.''; PubMed Europe PMC Scholia
  32. Cohen P, Graves HC, Peehl DM, Kamarei M, Giudice LC, Rosenfeld RG.; ''Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma.''; PubMed Europe PMC Scholia
  33. Holly J, Perks C.; ''The role of insulin-like growth factor binding proteins.''; PubMed Europe PMC Scholia
  34. Rajah R, Nachajon RV, Collins MH, Hakonarson H, Grunstein MM, Cohen P.; ''Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle.''; PubMed Europe PMC Scholia
  35. Baxter RC, Martin JL.; ''Structure of the Mr 140,000 growth hormone-dependent insulin-like growth factor binding protein complex: determination by reconstitution and affinity-labeling.''; PubMed Europe PMC Scholia
  36. Choi KY, Kyung YJ, Lee CY, Lee DH.; ''Characterization of insulin-like growth factor-free interaction between insulin-like growth factor binding protein 3 and acid labile subunit expressed from Xenopus oocytes.''; PubMed Europe PMC Scholia
  37. Twigg SM, Kiefer MC, Zapf J, Baxter RC.; ''Insulin-like growth factor-binding protein 5 complexes with the acid-labile subunit. Role of the carboxyl-terminal domain.''; PubMed Europe PMC Scholia
  38. Yan X, Forbes BE, McNeil KA, Baxter RC, Firth SM.; ''Role of N- and C-terminal residues of insulin-like growth factor (IGF)-binding protein-3 in regulating IGF complex formation and receptor activation.''; PubMed Europe PMC Scholia
  39. Laursen LS, Kjaer-Sorensen K, Andersen MH, Oxvig C.; ''Regulation of insulin-like growth factor (IGF) bioactivity by sequential proteolytic cleavage of IGF binding protein-4 and -5.''; PubMed Europe PMC Scholia
  40. Bach LA, Rechler MM.; ''Measurement of insulin-like growth factor (IGF)-II binding to purified IGF binding proteins 1-6: comparison of charcoal adsorption and high performance size exclusion chromatography.''; PubMed Europe PMC Scholia
  41. Twigg SM, Kiefer MC, Zapf J, Baxter RC.; ''A central domain binding site in insulin-like growth factor binding protein-5 for the acid-labile subunit.''; PubMed Europe PMC Scholia
  42. Overgaard MT, Boldt HB, Laursen LS, Sottrup-Jensen L, Conover CA, Oxvig C.; ''Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase.''; PubMed Europe PMC Scholia
  43. Gibson TL, Cohen P.; ''Inflammation-related neutrophil proteases, cathepsin G and elastase, function as insulin-like growth factor binding protein proteases.''; PubMed Europe PMC Scholia
  44. Angelloz-Nicoud P, Lalou C, Binoux M.; ''Prostate carcinoma (PC-3) cell proliferation is stimulated by the 22-25-kDa proteolytic fragment (1-160) and inhibited by the 16-kDa fragment (1-95) of recombinant human insulin-like growth factor binding protein-3.''; PubMed Europe PMC Scholia
  45. Lalou C, Lassarre C, Binoux M.; ''Isolation and characterization of proteolytic fragments of insulin-like growth factor-binding protein-3.''; PubMed Europe PMC Scholia
  46. Tagliabracci VS, Wiley SE, Guo X, Kinch LN, Durrant E, Wen J, Xiao J, Cui J, Nguyen KB, Engel JL, Coon JJ, Grishin N, Pinna LA, Pagliarini DJ, Dixon JE.; ''A Single Kinase Generates the Majority of the Secreted Phosphoproteome.''; PubMed Europe PMC Scholia
  47. Schneider MR, Zhou R, Hoeflich A, Krebs O, Schmidt J, Mohan S, Wolf E, Lahm H.; ''Insulin-like growth factor-binding protein-5 inhibits growth and induces differentiation of mouse osteosarcoma cells.''; PubMed Europe PMC Scholia
  48. Campbell EJ, Silverman EK, Campbell MA.; ''Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity.''; PubMed Europe PMC Scholia
  49. Firth SM, Clemmons DR, Baxter RC.; ''Mutagenesis of basic amino acids in the carboxyl-terminal region of insulin-like growth factor binding protein-5 affects acid-labile subunit binding.''; PubMed Europe PMC Scholia
  50. Mohan S, Baylink DJ.; ''IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms.''; PubMed Europe PMC Scholia
  51. Baxter RC, Bayne ML, Cascieri MA.; ''Structural determinants for binary and ternary complex formation between insulin-like growth factor-I (IGF-I) and IGF binding protein-3.''; PubMed Europe PMC Scholia
  52. Angelloz-Nicoud P, Binoux M.; ''Autocrine regulation of cell proliferation by the insulin-like growth factor (IGF) and IGF binding protein-3 protease system in a human prostate carcinoma cell line (PC-3).''; PubMed Europe PMC Scholia
  53. Marinaro JA, Neumann GM, Russo VC, Leeding KS, Bach LA.; ''O-glycosylation of insulin-like growth factor (IGF) binding protein-6 maintains high IGF-II binding affinity by decreasing binding to glycosaminoglycans and susceptibility to proteolysis.''; PubMed Europe PMC Scholia
  54. Okabe E, Kajihara J, Usami Y, Hirano K.; ''The cleavage site specificity of human prostate specific antigen for insulin-like growth factor binding protein-3.''; PubMed Europe PMC Scholia
  55. Wolf E, Lahm H, Wu M, Wanke R, Hoeflich A.; ''Effects of IGFBP-2 overexpression in vitro and in vivo.''; PubMed Europe PMC Scholia
  56. Andrade D, Assis DM, Santos JA, Alves FM, Hirata IY, Araujo MS, Blaber SI, Blaber M, Juliano MA, Juliano L.; ''Substrate specificity of kallikrein-related peptidase 13 activated by salts or glycosaminoglycans and a search for natural substrate candidates.''; PubMed Europe PMC Scholia
  57. Baxter RC, Meka S, Firth SM.; ''Molecular distribution of IGF binding protein-5 in human serum.''; PubMed Europe PMC Scholia
  58. Cohen P, Peehl DM, Graves HC, Rosenfeld RG.; ''Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease.''; PubMed Europe PMC Scholia
  59. Payet LD, Wang XH, Baxter RC, Firth SM.; ''Amino- and carboxyl-terminal fragments of insulin-like growth factor (IGF) binding protein-3 cooperate to bind IGFs with high affinity and inhibit IGF receptor interactions.''; PubMed Europe PMC Scholia
  60. Gyrup C, Oxvig C.; ''Quantitative analysis of insulin-like growth factor-modulated proteolysis of insulin-like growth factor binding protein-4 and -5 by pregnancy-associated plasma protein-A.''; PubMed Europe PMC Scholia
  61. Laursen LS, Overgaard MT, Søe R, Boldt HB, Sottrup-Jensen L, Giudice LC, Conover CA, Oxvig C.; ''Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A.''; PubMed Europe PMC Scholia
  62. Siwanowicz I, Popowicz GM, Wisniewska M, Huber R, Kuenkele KP, Lang K, Engh RA, Holak TA.; ''Structural basis for the regulation of insulin-like growth factors by IGF binding proteins.''; PubMed Europe PMC Scholia
  63. Lee KO, Oh Y, Giudice LC, Cohen P, Peehl DM, Rosenfeld RG.; ''Identification of insulin-like growth factor-binding protein-3 (IGFBP-3) fragments and IGFBP-5 proteolytic activity in human seminal plasma: a comparison of normal and vasectomized patients.''; PubMed Europe PMC Scholia
  64. Fielder PJ, Rosenfeld RG, Graves HC, Grandbois K, Maack CA, Sawamura S, Ogawa Y, Sommer A, Cohen P.; ''Biochemical analysis of prostate specific antigen-proteolyzed insulin-like growth factor binding protein-3.''; PubMed Europe PMC Scholia

History

View all...
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
CTSGProteinP08311 (Uniprot-TrEMBL) After secretion Cathepsin G is extracellular and associated with the plasma membrane.
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Cathepsin GR-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.
IGF1 ProteinP05019 (Uniprot-TrEMBL)
IGF1,2R-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)
MMP1,2R-HSA-381470 (Reactome)
PAPPA,PAPPA2R-HSA-381483 (Reactome)
PLG(20-580) ProteinP00747 (Uniprot-TrEMBL)
PLG(581-810) ProteinP00747 (Uniprot-TrEMBL)
PlasminComplexR-HSA-158770 (Reactome)
Prostate Specific AntigenR-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

View all...
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)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP2799"
Personal tools