Themammaliancalpaingenefamilycurrentlycontains13distinctlargesubunitproductsmostofwhichcomplexwithoneoftwosmaller30kDasubunits.(AnexcellentintroductiontothecalpainfamilycanbefoundonawebsitecreatedbyValeryThompsonhttp://ag.arizona.edu/calpains/index.html)Oneofthemostcarefullystudiedfunctionsofthecalpainsistheregulationofintegrin-mediatedcellmigration.CalpainsdigeststhelinksbetweentheactinCytoskeletonandseveralfocaladhesioncomplexproteins;talin,paxillinandfocaladhesionkinase.Thereleasefromthefocaladhesioncomplexfacilitatesmigration.Calpestatinisaninhibitorexpressedinmostcells.Calpestatinbindsthefourinhibitorydomainsofcalpain.Releasefromcalpestatindoesnotactivatecalpain.Activationrequiresadditionalsignaling,coactivatorsandanappropriatecalciumconcentration.Duringcellmigrationcalpain1(mu-calpain)actsattheleADIngedgeasaresponsetointegrinsignalsorcalciumfluxuationsduetothestretchactivatedcalciumchannels.Calpain1cleavesthetargetproteins,talin,exzrin,paxillinandthecytoplasmictailoftheintegrinsB1(a)andB3(b)toreleasetheadhesionandformnewadhesions.Calpain2(M-calpain)isbelievedtobemembraneboundandfunctionsatthetrailingedgeofthemigratingcelltocleavetheintegrinsinresponsetogrowthfactorreceptorsignals.PKAfunctionstodownregulateorinhibitcalpain2.Diseaserelatednotes:InAlzheimersdisease,amyloidpeptidesinterferewithcalpainactivitycausingamislocalizationofcdk5.Deregulatedcdk5hyperphosphorylatestaupromotingcelldeathinneurons(SeeDeregulationofCDK5inAlzheimer’sDisease).Mutationsinthemusclespecificcalpainp94leadtoLimbGirdlemusculardystrophy2A(LGMD2A).Overactivityofcalpainsduetoelevatedcalciumleadstotissuedamageintheheartandbrain(SeereferenceMoldoveanuetal.)

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REFERENCES:BialkowskaK,KulkarniS,DuX,GollDE,SaidoTC,FoxJE.Evidencethatbeta3integrin-inducedRacactivationinvolvesthecalpain-dependentformationofintegrinclustersthataredistinctfromthefocalcomplexesandfocaladhesionsthatformasRacandRhoAbecomeactive.JCellBiol.2000Oct30;151(3):685-96.GladingA,LauffenburgerDA,WellsA.Cuttingtothechase:calpainproteasesincellmotility.TrendsCellBiol.2002Jan;12(1):46-54.Review.GladingA,UberallF,KeyseSM,LauffenburgerDA,WellsA.MembraneproximalERKsignalingisrequiredforM-calpainactivationdownstreamofepidermalgrowthfactorreceptorsignaling.JBiolChem.2001Jun29;276(26):23341-8.KlemkeRL,CaiS,GianniniAL,GallagherPJ,deLanerolleP,ChereshDA.Regulationofcellmotilitybymitogen-activatedproteinkinase.JCellBiol.1997Apr21;137(2):481-92.KulkarniS,SaidoTC,SuzukiK,FoxJE.Calpainmediatesintegrin-inducedsignalingatapointupstreamofRhofamilymembers.JBiolChem.1999Jul23;274(30):21265-75.MoldoveanuT,HosfieldCM,LimD,ElceJS,JiaZ,DaviesPL.ACa(2+)switchalignstheactivesiteofcalpain.Cell.2002Mar8;108(5):649-60.Propertiesofthecalpains.http://ag.arizona.edu/calpains/physical_properties.html

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