Mitogen-activatedprotein(MAP)kinasesareimportantplayersinsignaltransductionpathwaysactivatedbyarangeofstimuliandmediateanumberofphysiologicalandpathologicalchangesincellfunction.TherearethreemajorsubgroupsintheMAPKfamily:ERK,p38,andJNK/SAPK.ERKisactivatedmainlybymitogenicstimuli,whereasp38andJNK/SAPKareactivatedmainlybystressstimuliorinflammatorycytokines.MAPkinasesarepartofathree-tieredphosphorylationcascadeandMAPkinasephosphorylationonathreonineandtyrosineresiduelocatedwithintheactivationloopofkinasesuBDomainVIIIresultsinactivation.However,thisprocessisreversIBLeeveninthecontinuedpresenceofactivatingstimuli,indicatingthatproteinphosphatasesprovideanimportantmechanismforMAPkinasecontrol.Dualspecificityphosphatases(DSP’s)fromtyrosinephosphatase(PTP)genesuperfamilyareselectivefordephosphorylatingthecriticalphosphothreonineandphosphotyrosineresidueswithinMAPkinases.TenmembersofdualspecificityphosphatasesspecificallyactingonMAPKs,termedMAPKphosphatases(MKPs),havebeenreported.TheysharesequencehomologyandarehighlyspecificforMAPK’sbutdifferinthesubstratespecificity,tissuedistribution,subcellularlocalization,andinducibilitybyextracellularstimuli.MKPshavebeenshowntoplayimportantrolesinregulatingthefunctionoftheMAPKfamily.DSPgeneexpressionisinducedstronglybyvariousgrowthfactorsand/orcellularstresses.Expressionofsomegenefamilymembers,includingCL100/MKP-1,hVH-2/MKP-2,andPAC1,isdependentatleastinpartonMAPkinaseactivationprovidingnegativefeedbackfortheinducingMAPkinaseorforregulatorycrosstalkbetweenparallelMAPkinasepathways.DSPsarelocalizedtodifferentsubcellularcompartmentsandcertainfamilymembersappearhighlyselectiveforinactivatingdistinctMAPkinaseisoforms.ThisenzymaticspecificityisduetocatalyticactivationoftheDSPphosphataseaftertightbindingofitsamino-terminaltothetargetMAPkinase.Thus,DSPphosphatasesprovideasophisticatedmechanismfortargetedinactivationofselectedMAPkinaseactivities.

Contributor:A.Konev,PhD

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