Fibroblastgrowthfactors(FGFs)compriseafamilyofatleast23structurallyrelatedproteinsthatareinvolvedinamultitudeofphysiologicalandpathologicalcellularprocessesincluding:cellgrowth,proliferationanddifferentiation,angiogenesis,chemotaxis,apoptosis,woundhealingandtumOrigenesis(1,2).TheBIOLOGicalactivitiesoftheFGFsaremediatedbyafamilyoftypeItransmembranetyrosinekinases(3).FourdistinctgenesencodingcloselyrelatedFGFreceptors,FGFR1-4,havebeenidentified(4).TheFGFRshaveseveralalternativelysplicedisoformsthatexhibitvariABIlityinligandaffinity,expressionpatterns,andsignalingproperties(5-10). 

HeparinorheparinsulfateproteoglycansareimportantcofactorsmediatingtheinteractionofFGFwithFGFRs(11-14).BindingofFGFtoFGFR3,resultsinreceptordimerization,followedbytrans-autophosphorylationofseveraltyrosineresiduesinthetyrosinekinasedomain(7,12,15).Structurally,theextracellularportionofFGFR3containsthreeimmunoglobulin(Ig)domains;thefirsttwoareseparatedbyastretchofacidicaminoacidstermedtheacidbox(3).FGFR3containsasingletransmembranedomainanddualintracellulartyrosinekinasedomains(3).

Duringhumandevelopment,FGFR3expressionisenrichedinbrain,lungintestine,kidney,skin,growthplate,andcalvarialbone(16).PointmutationsinFGFR3havebeendescribedforseveralskeletaldisorders,includinghypochondroplasia(17),thanatophoricdysplasia(18),SADDAN(severeachondroplasiawithdevelopmentaldelayandacanthosisnigricans)(19),craniosynostosis(20)andCrouzonsyndromewithacanthosisnigricans(21).Consistentwitharoleinskeletaldevelopment,morethan97%ofindividualswithachondroplasia,themostcommonformofdwarfism,exhibitaGly380ArgactivatingmutationintheFGFR3transmembranedomain(22).Aswithmanyothergrowthfactorreceptors,activatingmutationsinFGFR3canbeoncogenic(23).Forexample,FGFR3mutationshavebeenidentifiedincolorectal(24),andbladder(25)cancers.Inaddition,about20%ofmultiplemyelomacasesandderivedcelllinesexhibitachromosomaltranslocationeventthatresultsintheexpressionofFGFR3ontheplasmacellsurface(26-28).ThecomplexpatternsofexpressionoftheFGFRsaswellasthespecificityoftheirinteractionswiththevariousFGFligandfamilymembersareactiveareasofinvestigation.

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