Her2orERBB2belongstoaclassofproteinshavinghighhomologywithepidermalgrowthfactorreceptor(EGFRorERBB1).Itencodesaproteinwiththemolecularweightof185KDa.UnlikeothermembersofEGFRfamily,noligandforHer2hasbeenfoundanditusuallyassociateswithmembersofERBB1familytoformfunctionalheterodimers.IthasbeenshownthatitcanformdimerswithERBB(EGFR),ERBB3andERBB4aswellasgp130subunitsofIL-6receptor.Inatleastsomecelltypes,theassociationbetweengp130andHRBB2isessentialforHRBB2-ERBB3phosphorylationandsubsequentMAPkinasesignaling.AlthoughERBB1canformhomodimers,thesignalingforERBB1isusuallytransientandthereceptorundergoesinternalizationafterligandbindingandactivation.EGFR-HER2complexincreasesthesignalingcapacityofEGFRbyincreasingtheligandaffinityaswellastherecyclingoftheheterodimer.OfalltheERBBheterodimers,ERBB2-ERBB3heterodimersperhapselicitthestrongestsignal.RemovingERBB3fromthecellhasadrasticeffectonERBB2mediatedsignalinganddownstreameffectors.TheclinicalimportanceofHER2cannotbeoverstated.Inaddition,monoclonalantibody(Herceptin)againstthisreceptorhasbeenshowntobeaneffectivetreatmentofbreastcancerpatientswhohaveahighlevelofHER2overexpression.

Contributor:Yen-LiangChen,PhD

REFERENCES:ArteagaCL.OverviewofepidermalgrowthfactorreceptorBIOLOGyanditsroleasatherapeutictargetinhumanneoplasia.SeminOncol.2002Oct;29(5Suppl14):3-9.BadacheA,HynesNE.Interleukin6inhibitsproliferationand,incooperationwithanepidermalgrowthfactorreceptorautocrineloop,increasesmigrationofT47Dbreastcancercells.CancerRes.2001Jan1;61(1):383-91.HolbroTetal.TheErbBreceptorsandtheirroleincancerprogression.ExpCellRes.2003Mar10;284(1):99-110.HolbroTetal.TheErbB2/ErbB3heterodimerfunctionsasanoncogenicunit:ErbB2requiresErbB3todrivebreasttumorcellproliferation.ProcNatlAcadSciUSA.2003Jul22;100(15):8933-8.JandaEetal.OncogenicRas/Her-2mediatehyperproliferationofpolarizedepithelialcellsin3DculturesandrapidtumorgrowthviathePI3Kpathway.Oncogene.2002Aug1;21(33):5148-59.JohnstonSetal.Integrationofsignaltransductioninhibitorswithendocrinetherapy:anapproachtoovercominghormoneresistanceinbreastcancer.ClinCancerRes.2003Jan;9(1pt2):524S-32S.LindbergLEetal.c-erbB2-induceddisruptionofmatrixadhesionandmorphogenesisrevealsanovelroleforproteinkinaseBasanegativeregulatorofalpha(2)beta(1)integrinfunction.MolBiolCell.2002Aug;13(8):2894-908.QiuYetal.RequirementofErbB2forsignallingbyinterleukin-6inprostatecarcinomacells.Nature.1998May7;393(6680):83-5.VadlamudiRKetal.HeregulinandHER2signalingselectivelyactivatesc-Srcphosphorylationattyrosine215.FEBSLett.2003May22;543(1-3):76-80.VijapurkarUetal.Rolesofmitogen-activatedproteinkinaseandphosphoinositide3"-kinaseinErbB2/ErbB3coreceptor-mediatedheregulinsignaling.ExpCellRes.2003Apr1;284(2):291-302.