What is a Kinase – Linked receptor? Theyarereceptorscategoryofreceptors,whichspanthecellmembraneandhavecomponentsontheoutsideandinsideofthecell.Theyareactivatedbysignallingmoleculecalledligandsbindstothereceptorregion,AKA,theN-terminuscausingacascadeofreactions[1].Tyrosineattachedtotheintracellularcomponentofthereceptoris,AKAtheC-terminus,whichgetsphosphorylatedbyATP(commonlyreferredtoas‘cellenergycurrency’),whichdonatesaphosphategrouptotheTyrosine,activatingit.Theactivatedtyrosinethenactivatesreplyproteins,whichcausesignaltransduction,proteinproductionandcellgrowth[1].Essentiallythisprocessinvolvesasignallingmoleculeandreceptor,whichbindtogetherandactivatepathwayswhichresultinproteinsynthesisandcellgenerationorreproduction.Thinkofthisasapuzzle,where1piececonnectstoanotherandanotherandanotherandfinallyyouseethebiggerpicture.Letsbreakthisdowninto4basicsteps:

1. Ligandbindstoreceptor

Figure1:Signallingmoleculecomesandbindstothereceptoronthesurfaceofthecell

2. Tworeceptorsbindtogethertoformadimer

Figure2:Twoactivatedreceptorsjointogetherandformwhatiscalledadimer(2unitsjoinedtogether)

3. Phosphorylation

Figure3:ATP(cellsenergycurrency)donatesaphosphategrouptoTyrosineresultinginactivation

4. Relayproteinsareactivatedandcausecellularresponse

Figure4:Inactivereplayproteinsareactivated,generatingdifferentresponsessuchas,productionofdifferentproteinsandcellproliferation(growthandreproduction)

Kinase – Linked Receptors: Complicated Little Puzzle

By: Riva Shirol

Image1:Ligandattachedtoacellreceptor

Types of Kinase – linked receptors Nowthatwe’vetalkedaboutwhattheyareandhowtheywork,letstakealookat3examples.

Figure5:3mostcommonexamplesofKinaselinkedreceptors,withtheirgeneralstructureandsubunitsidentified.TheimagealsoshowshowInsulinreceptorsexistasdimersandtheother2existassingleunitreceptors.

1. Epidermalgrowthfactor(EGF)receptorsFirstofthreeexamples,EGFreceptorsareonEpidermalcells.Thesecellscoveralltheinternalandexternalsurfacesofthebody.GrowthfactormoleculesactiveEGFreceptors,resultinginmaturationofthecellleadingtocelldifferentiation.Thereceptorsarealsopresentonthesurfaceofneuronswithinthecerebralandcerebellumofthebrainandonothercellsofthecentralnervoussystem(CNS)[2].

2. InsulinreceptorSecondexamplesareinsulinreceptors.Insulinisahormone,whichisreleasedbythepancreases,andplaysthecrucialroleinglucosemetabolism[3].Funfact:Insulinreceptorsexistasdimersandwhileothersarelonereceptorsandneedtobeactivatedinordertoformdimers.WhenaninsulinreceptorisactivatedbyInsulinitleadstoadecreaseinbloodglucoseconcentrationbyallowingglucosetobestoredinliverandfatcells.InsulinalsoallowsglucosetotravelothercellssothatitmaybeusedtoproduceenergyintheformofATP[4].

3. Plateletderivedgrowthfactor(PDGF)Andhereyouhavethefinalexample.Plateletsarecellfragmentsthatcirculateinbloodplasmawhichenableclottingwhenabrokenbloodvesselorcutorisdetected[5].PDGFreceptors-whenactivatedinhibitorpromoteembryonicdevelopment,formationofbloodvesselsandcellproliferation[6].CASE STUDY à HER-2 - and Trastuzumab Thisisaninterestinglittleexampleofaveryspecificreceptor,letsseeifyoucankeepup.Humanepidermalgrowthfactorreceptor2orHER–2,isakinase-linkedreceptorexpressedonhealthybreastcells,about2000receptorsexpressedpercell.Thesereceptorswhenactivatedleadtogeneexpressionandcellproliferation[13].Whentoomanyofthesereceptorsareexpressed,stimulationcanleadtouncontrolledcellgrowthresultingintumors[7].Interestingfact:1in5breastcancersarearesultofoverexpressionofHER-2[8].Buthere’sthegoodnews,adrugcalledTrastuzumaborHerceptin,whichcontainsantibodiesthatattachandblocktheHER-2receptors,preventsignalingmoleculesfromattachingandstimulatingit,thuspreventingthecellfrommaturinganduncontrollablyproliferating,destroyedthecancertissue[9].

Figure6:Herceptin(Trastuzumab)blocksreceptorandpreventsreceptorsfromformingdimersthereforepreventingsignaltransduction,transcription(proteinproduction)andcellproliferation,preventingcelldivision(reproduction),Yay!

References [1]natureEducation,2014,RTK,Scitable,viewed2May2018,<https://www.nature.com/scitable/topicpage/rtk-14050230>[2]Wong,R.,Guillaud,L.,2004,‘TheroleofepidermalgrowthfactoranditsreceptorsinmammalianCNS’Pubmed,viewed3May2018,<https://www.ncbi.nlm.nih.gov/pubmed/15110798>[3]Meyts,P.2016,‘TheInsulinReceptorandItsSignalTransductionNetwork’,NCBI,viewed3May2018,<https://www.ncbi.nlm.nih.gov/books/NBK378978/>[4]Ballotti,R.,Le,Y.,Gammeltoft,S.,Obberghen,E.1989,‘Insulinreceptor:tyrosinekinaseactivityandinsulinaction’viewed3May2018,<https://www.ncbi.nlm.nih.gov/pubmed/2534271>[5]Williams,M.n.d.,‘WhatarePlateletsandWhyareTheyImportant?’,JohnHopkinsMedicine,viewed3May2018,<https://www.hopkinsmedicine.org/heart_vascular_institute/clinical_services/centers_excellence/womens_cardiovascular_health_center/patient_information/health_topics/platelets.html>[6]SinoBiological,n.d.,‘Platelet-derivedGrowthFactor(PDGF)Receptors’,viewed4May2018,<https://www.sinobiological.com/Platelet-derived-Growth-Factor-PDGF-Receptors-a-6628.html>[7]Gajria,D.,Chandarlapaty,S.,2011‘HER2-amplifiedbreastcancer:mechanismsoftrastuzumabresistanceandnoveltargetedtherapies’PMC,viewed4May2018,<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092522/>[8]Moynihan,T.2018,‘AfriendofminehasHER2-positivebreastcancer.Canyoutellmewhatthismeans?’,MayoClinic,viewed4May2018,<https://www.mayoclinic.org/breast-cancer/expert-answers/faq-20058066>[9]CancerAustralia,2018,‘Trastuzumab(Herceptin)’,AustralianGovernment,viewed10May2018,<https://canceraustralia.gov.au/affected-cancer/cancer-types/breast-cancer/treatment/what-does-treatment-breast-cancer-involve/targeted-therapies/types-targeted-therapy/trastuzumab-herceptin>

Images/ Figures [10]Image1:BesikEighty3,2018,n.d.,‘CellMembraneFunctionAndStructure-CellMembraneStructure’,viewed10May2018,<http://besik.eighty3.co/cell-membrane-structure/cell-membrane-function-and-structure.html>[11]Figure1-4:Traynor,A.n.d.,‘”WhattheCellwasthat?!"--TyrosineKinaseandCellSignalingby:Andrew,Colin,andGinger’,Tes,viewed2May2018,<https://www.tes.com/lessons/HziadL2dIeDLGw/what-the-cell-was-that-tyrosine-kinase-and-cell-signaling-by-andrew-colin-and-ginger>[12]Figure5:Heda,N.,2013,‘TypesofReceptors-Part2’,BforBiology,viewed3May2018,<http://namrataheda.blogspot.com.au/2013/02/types-of-receptors-part-2.html>[13]Figure6:Gemmete,J.,Mukherji,S.,2011,‘Trastuzumab(Herceptin)’,AmericanJournalofNeuroradiology,viewed10May2018,<http://www.ajnr.org/content/32/8/1373>