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SRC,protooncogene
tyrosineproteinkinase

Srcregulation:conformationalopeningandactivation
ReprintedfromBiochimBiophysActa1602(2),M.Frame,SrcinCancer,114130,2002,with
permissionfromElsevier,PMID:12020799

HowSrcworks

TheSrcproteinhasthreemajordomains,SH2(forSrchomology2),SH3,andthekinase
catalyticdomain(orSH1),asshownabove.SH2andSH3bothplayapartinproteinprotein
interactions,whilethekinasecatalyticdomaincontainsthekinaseactivesite.Srccanbeswitched
fromaninactivetoanactivestatethroughcontrolofitsphosphorylationstate,orthroughprotein
interactions.TherearetwomajorphosphorylationsitesonSrc:oneisatTyr416(orY416),theother
atTyr527,asmarkedinthedrawingaboveforchickenSrc.Tyr416canbeautophosphorylated,
whichactivatesSrcbydisplacingthePTyr416fromthebindingpocket,allowingthesubstrateto
gainaccess.AmorecriticalsiteisTyr527,whichcanbephosphorylatedanddephosphorylatedby
variousproteins,suchasCSKkinase(phosphorylates),orSHP1phosphorylase(dephosphorylates).
PhosphorylationofTyr527inactivatesSrcthroughtheinteractionofPTyr527withtheSH2domain,
whicheffectivelyfoldsSrcupintoaclosed,inaccessiblebundle.DephosphorylationofTyr527
releasesthisbond,openingupthemoleculetoanactivestate.Proteininteractionsalsoacttoregulate
SrcbyeitherdirectlyactivatingSrc,orbymovingSrctositesofaction.Bothplateletderivedgrowth
factorandfocaladhesionkinaseareabletobindtotheSH2domain,causingSrctoopenupintothe
activeform.
ManyofthesubstratesthatSrccanphosphorylatewithitskinasedomainformpartof
signallingcascades.TheseincludeFakandCas,whichareimportantforintegrinsignalling,aswell
asShcandStat3,whichareinvolvedingrowthregulation.Signallingsystemsofteninvolveacascade
mechanismofsequentialphosphorylationanddephosphorylationofproteinsinthecascade,asoccurs
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here.

Srcfamilymembers

ConsideringthevitalroleSrcseemstoplayincellsignalling,scientistsweresurprisedtofind
thatmicedeficientinSrccouldsurvive.ThereasonforthisresultisthatSrcisoneofninemembers
inacloselyrelatedfamilythatcanoftencompensateforoneanother.OtherSrcfamilykinase
membersareFynandYes,whichlikeSrcarewidelyexpressed,andBlk,Fgr,Hck,Lck,Lyn,and
Yrk,whichareexpressedinspecifictissues.AlltheseproteinshavestructurallysimilarSH2,SH3
andkinasedomainsandarecapableofactingassignallingmoleculesinasimilarmannertoSrc.

WhenSrcgoeswrong

Undernormalcircumstances,Srcispredominantlyinactiveincells,beingswitchedononlyat
specifictimes.However,ifthefinebalancebetweenphosphorylationanddephosphorylationis
disrupted,changescanoccurinSrcactivitywithdrasticresults.Severalcancers,includingcolonand
breastcancer,havebeenassociatedwithanincreaseinSrcactivity.Infact,Srcwasfirstisolatedas
anoncogene,vSrc,fromthetransformingvirus,RousSarcomaVirus.vSrcwasfoundtolackthe
regionofthecellularprotein(cSrc)thatcontainsTyr527,makingitcontinuallyactive.
Inasimilarfashion,cSrccanbecomeabnormallyactive,eitherthroughmutationsincSrc
itself,orthroughmutationsinproteinsthatregulatecSrc.Inlatestagecoloncancers,mutationshave
beenreportedinthesrcgenethatcausethelossoftheregioncontainingTyr527,leadingtoSrcover
activity.ProteinsthatregulateSrchavealsobeenfoundatabnormallevelsincancercells,including
boththosethatactivateandthosethatinactivateSrc.ProteinssuchasPTPalpha,SHP1andPTP1B
thatactivateSrcbydephosphorylatingTyr527havebeendetectedatelevatedlevelsinvariouscancer
cells,includingepidermalandbreastcarcinomacells.Conversely,proteinssuchasCskandChkthat
inactivateSrcbyphosphorylationofTyr527havebeendetectedatreducedlevelsincertaincancer
cells.Assuch,proteinslikeCskandChkareconsideredtohaveatumoursuppressingability.
Withitsimportanceincellregulation,anditsimplicationincancer,Src,aswellasother
proteinkinases,hasbecomeanimportantdrugtargetinthebattleagainstcancer.

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