Wikipedia

Receptor tyrosine kinase

Receptor tyrosine kinases(RTKs) are the high-affinitycell surface receptorsfor many polypeptidegrowth factors,cytokines,andhormones.Of the 90 uniquetyrosine kinasegenesidentified in thehuman genome,58 encode receptor tyrosine kinase proteins.[1] Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types ofcancer.[2]Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression.[3]The receptors are generally activated by dimerization andsubstrate presentation.Receptor tyrosine kinases are part of the larger family ofprotein tyrosine kinases,encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as thenon-receptor tyrosine kinaseswhich do not possess transmembrane domains.[4]

receptor protein-tyrosine kinase
Identifiers
EC no.2.7.10.1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDBstructuresRCSB PDBPDBePDBsum
Gene OntologyAmiGO/QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
Identifiers
SymbolPkinase_Tyr
PfamPF07714
OPM superfamily186
OPM protein2k1k
Membranome3
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary

History

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The first RTKs to be discovered were the EGF and NGF receptors in the 1960s, but the classification of receptor tyrosine kinases was not developed until the 1970s.[5]

Classes

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Approximately 20 different RTK classes have been identified.[6]

  1. RTK class I (EGF receptor family) (ErbB family)
  2. RTK class II (Insulin receptorfamily)
  3. RTK class III(PDGF receptorfamily)
  4. RTK class IV (VEGF receptorsfamily)
  5. RTK class V (FGF receptorfamily)
  6. RTK class VI (CCK receptorfamily)
  7. RTK class VII (NGF receptorfamily)
  8. RTK class VIII (HGF receptorfamily)
  9. RTK class IX (Eph receptorfamily)
  10. RTK class X (AXL receptorfamily)
  11. RTK class XI (TIE receptorfamily)
  12. RTK class XII (RYK receptorfamily)
  13. RTK class XIII (DDR receptorfamily)
  14. RTK class XIV (RET receptorfamily)
  15. RTK class XV (ROS receptorfamily)
  16. RTK class XVI (LTK receptorfamily)
  17. RTK class XVII (ROR receptorfamily)
  18. RTK class XVIII (MuSK receptorfamily)
  19. RTK class XIX (LMR receptor)
  20. RTK class XX (Undetermined)

Structure

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Most RTKs are single subunit receptors but some exist asmultimeric complexes,e.g., theinsulin receptorthat forms disulfide linked dimers in the presence of hormone (insulin); moreover, ligand binding to the extracellular domain induces formation of receptor dimers.[7]Eachmonomerhas a single hydrophobictransmembrane-spanningdomaincomposed of 25 to 38amino acids,anextracellularN terminalregion, and anintracellularC terminalregion.[8]The extracellular N terminal region exhibits a variety of conserved elements including immunoglobulin (Ig)-like or epidermal growth factor (EGF)-like domains, fibronectin type III repeats, or cysteine-rich regions that are characteristic for each subfamily of RTKs; these domains contain primarily a ligand-binding site, which binds extracellularligands,e.g., a particulargrowth factororhormone.[2]The intracellular C terminal region displays the highest level of conservation and comprises catalytic domains responsible for thekinaseactivity of these receptors, which catalyses receptor autophosphorylation and tyrosine phosphorylation of RTK substrates.[2]

Kinase activity

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Akinaseis a type ofenzymethat transfersphosphategroups (see below) fromhigh-energydonor molecules, such asATP(see below) to specific target molecules (substrates); the process is termedphosphorylation.The opposite, an enzyme that removes phosphate groups from targets, is known as aphosphatase.Kinase enzymes that specifically phosphorylate tyrosine amino acids are termedtyrosine kinases.

When a growth factor binds to the extracellular domain of a RTK, itsdimerizationis triggered with other adjacent RTKs.Dimerizationleads to a rapid activation of the protein's cytoplasmic kinase domains, the first substrate for these domains being the receptor itself. The activated receptor as a result then becomes autophosphorylated on multiple specific intracellulartyrosineresidues.

Signal transduction

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Through diverse means, extracellular ligand binding will typically cause or stabilize receptor dimerization. This allows atyrosinein the cytoplasmic portion of each receptor monomer to betrans-phosphorylated by its partner receptor, propagating a signal through the plasma membrane.[9]The phosphorylation of specific tyrosine residues within the activated receptor creates binding sites forSrc homology 2(SH2) domain- andphosphotyrosinebinding (PTB) domain-containing proteins.[10][11] Specific proteins containing these domains includeSrcandphospholipase Cγ. Phosphorylation and activation of these two proteins on receptor binding lead to the initiation ofsignal transductionpathways. Other proteins that interact with the activated receptor act asadaptor proteinsand have no intrinsic enzymatic activity of their own. These adaptor proteins link RTK activation to downstreamsignal transductionpathways, such as theMAP kinase signalling cascade.[2]An example of a vital signal transduction pathway involves the tyrosine kinase receptor, c-met, which is required for the survival and proliferation of migrating myoblasts duringmyogenesis.A lack of c-met disrupts secondary myogenesis and—as in LBX1—prevents the formation of limb musculature. This local action of FGFs (Fibroblast Growth Factors) with their RTK receptors is classified asparacrine signalling.As RTK receptors phosphorylate multipletyrosineresidues, they can activate multiplesignal transductionpathways.

Families

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Epidermal growth factor receptor family

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Further information:ErbB

The ErbB protein family or epidermal growth factor receptor (EGFR) family is a family of four structurally related receptor tyrosine kinases. Insufficient ErbB signaling in humans is associated with the development ofneurodegenerative diseases,such asmultiple sclerosisandAlzheimer's disease.[12] In mice, loss of signaling by any member of the ErbB family results inembryoniclethality with defects in organs including thelungs,skin,heart,andbrain.Excessive ErbB signaling is associated with the development of a wide variety of types of solidtumor.ErbB-1 and ErbB-2 are found in many humancancersand their excessive signaling may be critical factors in the development andmalignancyof thesetumors.[13]

Fibroblast growth factor receptor (FGFR) family

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Further information:fibroblast growth factor receptor

Fibroblast growth factorscomprise the largest family of growth factor ligands at 23 members.[14]The naturalalternate splicingof four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 differentisoformsof FGFR.[15] These isoforms vary in their ligand binding properties and kinase domains; however, all share a common extracellular region composed of threeimmunoglobulin(Ig)-like domains (D1-D3), and thus belong to theimmunoglobulin superfamily.[16] Interactions with FGFs occur via FGFR domains D2 and D3. Each receptor can be activated by several FGFs. In many cases, the FGFs themselves can also activate more than one receptor. This is not the case with FGF-7, however, which can activate only FGFR2b.[15] A gene for a fifth FGFR protein, FGFR5, has also been identified. In contrast to FGFRs 1-4, it lacks a cytoplasmic tyrosine kinase domain, and one isoform, FGFR5γ, only contains the extracellular domains D1 and D2.[17]

Vascular endothelial growth factor receptor (VEGFR) family

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Further information:Vascular endothelial growth factor

Vascular endothelial growth factor(VEGF) is one of the main inducers ofendothelial cellproliferation and permeability ofblood vessels.Two RTKs bind to VEGF at the cell surface, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).[18]

The VEGF receptors have an extracellular portion consisting of sevenIg-like domains so, like FGFRs, belong to the immunoglobulin superfamily. They also possess a single transmembrane spanning region and an intracellular portion containing a splittyrosine-kinasedomain. VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). A third receptor has been discovered (VEGFR-3); however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediateslymphangiogenesisin response to VEGF-C and VEGF-D.

RET receptor family

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Further information:RET proto-oncogene

The naturalalternate splicingof theRETgeneresults in the production of 3 differentisoformsof the protein RET. RET51, RET43, and RET9 contain 51, 43, and 9amino acidsin theirC-terminaltail, respectively.[19]The biological roles ofisoformsRET51 and RET9 are the most well studiedin vivo,as these are the most common isoforms in which RET occurs.

RET is the receptor for members of theglial cell line-derived neurotrophic factor(GDNF) family of extracellularsignalling moleculesorligands(GFLs).[20]

In order to activate RET, first GFLs must form acomplexwith aglycosylphosphatidylinositol(GPI)-anchoredco-receptor.The co-receptors themselves are classified as members of the GDNF receptor-α (GFRα) protein family. Different members of the GFRα family (GFRα1-GFRα4) exhibit a specific binding activity for a specific GFLs.[21] Upon GFL-GFRα complex formation, the complex then brings together two molecules of RET, triggeringtrans-autophosphorylationof specifictyrosineresidues within thetyrosine kinasedomain of each RET molecule.Phosphorylationof thesetyrosinesthen initiates intracellularsignal transductionprocesses.[22]

Eph receptor family

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Further information:Eph receptor

Ephrin receptorsare the largest subfamily of RTKs.

Discoidin domain receptor (DDR) family

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Further information:DDR1

The DDRs are unique RTKs in that they bind tocollagensrather than soluble growth factors.[23]

Regulation

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The receptor tyrosine kinase (RTK) pathway is carefully regulated by a variety of positive andnegative feedbackloops.[24]Because RTKs coordinate a wide variety of cellular functions such as cell proliferation and differentiation, they must be regulated to prevent severe abnormalities in cellular functioning such as cancer and fibrosis.[25]

Protein tyrosine phosphatases

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Protein Tyrosine Phosphatase (PTPs) are a group of enzymes that possess a catalytic domain with phosphotyrosine-specific phosphohydrolase activity. PTPs are capable of modifying the activity of receptor tyrosine kinases in both a positive and negative manner.[26]PTPs can dephosphorylate the activated phosphorylated tyrosine residues on the RTKs[27]which virtually leads to termination of the signal. Studies involving PTP1B, a widely known PTP involved in the regulation of the cell cycle and cytokine receptor signaling, has shown to dephosphorylate the epidermal growth factor receptor[28]and the insulin receptor.[29]Some PTPs, on the other hand, are cell surface receptors that play a positive role in cell signaling proliferation. Cd45, a cell surface glycoprotein, plays a critical role in antigen-stimulated dephosphorylation of specific phosphotyrosines that inhibit the Src pathway.[30]

Herstatin

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Herstatin is an autoinhibitor of the ErbB family,[31]which binds to RTKs and blocks receptor dimerization and tyrosine phosphorylation.[27]CHO cells transfected with herstatin resulted in reduced receptor oligomerization, clonal growth and receptor tyrosine phosphorylation in response to EGF.[32]

Receptor endocytosis

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Activated RTKs can undergo endocytosis resulting in down regulation of the receptor and eventually the signaling cascade.[3]The molecular mechanism involves the engulfing of the RTK by a clathrin-mediated endocytosis, leading to intracellular degradation.[3]

Drug therapy

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RTKs have become an attractive target for drug therapy due to their implication in a variety of cellular abnormalities such as cancer, degenerative diseases and cardiovascular diseases. The United States Food and Drug Administration (FDA) has approved several anti-cancer drugs caused by activated RTKs. Drugs have been developed to target the extracellular domain or the catalytic domain, thus inhibiting ligand binding, receptor oligomerization.[33]Herceptin, a monoclonal antibody that is capable of binding to the extracellular domain of RTKs, has been used to treat HER2 overexpression in breast cancer.[34]

Small molecule inhibitors and monoclonal antibodies (approved by the US Food and Drug Administration) against RTKs for cancer therapy[3]
Small Molecule Target Disease Approval Year
Imatinib (Gleevec) PDGFR, KIT, Abl, Arg CML, GIST 2001
Gefitinib (Iressa) EGFR Esophageal cancer, Glioma 2003
Erlotinib (Tarceva) EGFR Esophageal cancer, Glioma 2004
Sorafenib (Nexavar) Raf, VEGFR, PDGFR, Flt3, KIT Renal cell carcinoma 2005
Sunitinib (Sutent) KIT, VEGFR, PDGFR, Flt3 Renal cell carcinoma, GIST, Endocrine pancreatic cancer 2006
Dasatinib (Sprycel) Abl, Arg, KIT, PDGFR, Src Imatinib-resistant CML 2007
Nilotinib (Tasigna) Abl, Arg, KIT, PDGFR Imatinib-resistant CML 2007
Lapatinib (Tykerb) EGFR, ErbB2 Mammary carcinoma 2007
Trastuzumab (Herceptin) ErbB2 Mammary carcinoma 1998
Cetuximab (Erbitux) EGFR Colorectal cancer, Head and neck cancer 2004
Bevacizumab (Avastin) VEGF Lung cancer, Colorectal cancer 2004
Panitumumab (Vectibix) EGFR Colorectal cancer 2006

+ Table adapted from "Cell signalling by receptor-tyrosine kinases," by Lemmon and Schlessinger's, 2010.Cell,141,p. 1117–1134.

See also

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References

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  1. ^Robinson DR, Wu YM, Lin SF (November 2000)."The protein tyrosine kinase family of the human genome".Oncogene.19(49):5548–57.doi:10.1038/sj.onc.1203957.PMID11114734.
  2. ^abcdZwick E, Bange J, Ullrich A (September 2001)."Receptor tyrosine kinase signalling as a target for cancer intervention strategies".Endocrine-Related Cancer.8(3):161–73.doi:10.1677/erc.0.0080161.PMID11566607.
  3. ^abcdLemmon MA, Schlessinger J (June 2010)."Cell signaling by receptor tyrosine kinases".Cell.141(7):1117–34.doi:10.1016/j.cell.2010.06.011.PMC2914105.PMID20602996.
  4. ^Hubbard SR, Till JH (2000). "Protein tyrosine kinase structure and function".Annual Review of Biochemistry.69:373–98.doi:10.1146/annurev.biochem.69.1.373.PMID10966463.
  5. ^Schlessinger, J. (3 March 2014)."Receptor Tyrosine Kinases: Legacy of the First Two Decades".Cold Spring Harbor Perspectives in Biology.6(3): a008912.doi:10.1101/cshperspect.a008912.PMC3949355.PMID24591517.
  6. ^Ségaliny, Aude I.; Tellez-Gabriel, Marta; Heymann, Marie-Françoise; Heymann, Dominique (2015)."Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers".Journal of Bone Oncology.4(1):1–12.doi:10.1016/j.jbo.2015.01.001.PMC4620971.PMID26579483.
  7. ^Lodish; et al. (2003).Molecular cell biology(5th ed.).
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  9. ^Lemmon MA,Schlessinger J(June 2010)."Cell signaling by receptor tyrosine kinases".Cell.141(7):1117–34.doi:10.1016/j.cell.2010.06.011.PMC2914105.PMID20602996.
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  11. ^Ren S, Yang G, He Y, Wang Y, Li Y, Chen Z (October 2008)."The conservation pattern of short linear motifs is highly correlated with the function of interacting protein domains".BMC Genomics.9:452.doi:10.1186/1471-2164-9-452.PMC2576256.PMID18828911.
  12. ^Bublil EM, Yarden Y (April 2007). "The EGF receptor family: spearheading a merger of signaling and therapeutics".Current Opinion in Cell Biology.19(2):124–34.doi:10.1016/j.ceb.2007.02.008.PMID17314037.
  13. ^Cho HS, Leahy DJ (August 2002)."Structure of the extracellular region of HER3 reveals an interdomain tether".Science.297(5585):1330–3.Bibcode:2002Sci...297.1330C.doi:10.1126/science.1074611.PMID12154198.S2CID23069349.
  14. ^Ornitz DM, Itoh N (2001)."Fibroblast growth factors".Genome Biology.2(3): REVIEWS3005.doi:10.1186/gb-2001-2-3-reviews3005.PMC138918.PMID11276432.
  15. ^abDuchesne L, Tissot B, Rudd TR, Dell A, Fernig DG (September 2006)."N-glycosylation of fibroblast growth factor receptor 1 regulates ligand and heparan sulfate co-receptor binding".The Journal of Biological Chemistry.281(37):27178–89.doi:10.1074/jbc.M601248200.PMID16829530.
  16. ^Coutts JC, Gallagher JT (December 1995). "Receptors for fibroblast growth factors".Immunology and Cell Biology.73(6):584–9.doi:10.1038/icb.1995.92.PMID8713482.S2CID28828504.
  17. ^Sleeman M, Fraser J, McDonald M, Yuan S, White D, Grandison P, Kumble K, Watson JD, Murison JG (June 2001). "Identification of a new fibroblast growth factor receptor, FGFR5".Gene.271(2):171–82.doi:10.1016/S0378-1119(01)00518-2.PMID11418238.
  18. ^Robinson CJ, Stringer SE (March 2001)."The splice variants of vascular endothelial growth factor (VEGF) and their receptors".Journal of Cell Science.114(Pt 5):853–65.doi:10.1242/jcs.114.5.853.PMID11181169.
  19. ^Myers SM, Eng C, Ponder BA, Mulligan LM (November 1995). "Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET".Oncogene.11(10):2039–45.PMID7478523.
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  21. ^Airaksinen MS, Titievsky A, Saarma M (May 1999). "GDNF family neurotrophic factor signaling: four masters, one servant?".Molecular and Cellular Neurosciences.13(5):313–25.doi:10.1006/mcne.1999.0754.PMID10356294.S2CID46427535.
  22. ^Arighi E, Borrello MG, Sariola H (2005). "RET tyrosine kinase signaling in development and cancer".Cytokine & Growth Factor Reviews.16(4–5):441–67.doi:10.1016/j.cytogfr.2005.05.010.PMID15982921.
  23. ^Fu HL, Valiathan RR, Arkwright R, Sohail A, Mihai C, Kumarasiri M, Mahasenan KV, Mobashery S, Huang P, Agarwal G, Fridman R (March 2013)."Discoidin domain receptors: unique receptor tyrosine kinases in collagen-mediated signaling".The Journal of Biological Chemistry.288(11):7430–7.doi:10.1074/jbc.R112.444158.PMC3597784.PMID23335507.
  24. ^Ostman A, Böhmer FD (June 2001). "Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases".Trends in Cell Biology.11(6):258–66.doi:10.1016/s0962-8924(01)01990-0.PMID11356362.
  25. ^Haj FG, Markova B, Klaman LD, Bohmer FD, Neel BG (January 2003)."Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B".The Journal of Biological Chemistry.278(2):739–44.doi:10.1074/jbc.M210194200.PMID12424235.
  26. ^Volinsky N, Kholodenko BN (August 2013)."Complexity of receptor tyrosine kinase signal processing".Cold Spring Harbor Perspectives in Biology.5(8): a009043.doi:10.1101/cshperspect.a009043.PMC3721286.PMID23906711.
  27. ^abLedda F, Paratcha G (February 2007)."Negative Regulation of Receptor Tyrosine Kinase (RTK) Signaling: A Developing Field".Biomarker Insights.2:45–58.doi:10.1177/117727190700200029.PMC2717834.PMID19662191.
  28. ^Flint AJ, Tiganis T, Barford D, Tonks NK (March 1997)."Development of" substrate-trapping "mutants to identify physiological substrates of protein tyrosine phosphatases".Proceedings of the National Academy of Sciences of the United States of America.94(5):1680–5.Bibcode:1997PNAS...94.1680F.doi:10.1073/pnas.94.5.1680.PMC19976.PMID9050838.
  29. ^Kenner KA, Anyanwu E, Olefsky JM, Kusari J (August 1996)."Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling".The Journal of Biological Chemistry.271(33):19810–6.doi:10.1074/jbc.271.33.19810.PMID8702689.
  30. ^Hermiston ML, Zikherman J, Zhu JW (March 2009)."CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells".Immunological Reviews.228(1):288–311.doi:10.1111/j.1600-065X.2008.00752.x.PMC2739744.PMID19290935.
  31. ^Justman QA, Clinton GM (2002)."Herstatin, an autoinhibitor of the human epidermal growth factor receptor 2 tyrosine kinase, modulates epidermal growth factor signaling pathways resulting in growth arrest".The Journal of Biological Chemistry.277(23):20618–24.doi:10.1074/jbc.M111359200.PMID11934884.
  32. ^Azios NG, Romero FJ, Denton MC, Doherty JK, Clinton GM (August 2001). "Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor".Oncogene.20(37):5199–209.doi:10.1038/sj.onc.1204555.PMID11526509.
  33. ^Seshacharyulu P, Ponnusamy MP, Haridas D, Jain M, Ganti AK, Batra SK (January 2012)."Targeting the EGFR signaling pathway in cancer therapy".Expert Opinion on Therapeutic Targets.16(1):15–31.doi:10.1517/14728222.2011.648617.PMC3291787.PMID22239438.
  34. ^Carlsson J, Nordgren H, Sjöström J, Wester K, Villman K, Bengtsson NO, Ostenstad B, Lundqvist H, Blomqvist C (June 2004)."HER2 expression in breast cancer primary tumours and corresponding metastases. Original data and literature review".British Journal of Cancer.90(12):2344–8.doi:10.1038/sj.bjc.6601881.PMC2409528.PMID15150568.
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