Ato o orsodne([email protected]) correspondence for *Author St., 15th USA. W. of 46202, 320 Institute IN Building, Medicine, Indianapolis, Research of Neuroscience School Research, University Indiana Psychiatric Genetics, Molecular & Medical d5atvt nteban–mlil ah fregulation of paths multiple Shah – Kavita brain the in activity Cdk5 COMMENTARY ß 2 1 discovery The 1991). al., Spottswood, et and high Tsai 1991; (Elledge al., Cdk2 a et its Ninomiya-Tsuji from kinase 1991; cloned was be of library to 1987). family cDNA because Cdk Nurse, human the and of Cdk1) homolog (Lee human Cdc2 second as kinase The 2 yeast known fission cycle with division officially homology cell termed now was (Cdc2; and yeast, in complementation proximal at phases specific Arg cycle. in roles cell and indispensable of play in Lys and expressed highly cells residues are a proliferating Cdks with positions. basic downstream sites, and the Thr-Pro upstream or for Ser-Pro al., phosphorylate preference Cdk11) et Cdks (Malumbres – Cdk13) All (Cdk1 (Cdk12, activated. 2009). members Cdks be family classic new to 11 two order and includes in currently subunits family cyclin This that specific kinases with protein Ser/Thr associate are (Cdks) kinases Cyclin-dependent Introduction Synaptogenesis growth, Neuronal Axonal signalling, migration, Pain memory, and Learning plasticity, Synaptic disease, Alzheimer’s Neurodegeneration, Cyclins, effective p35, p25, Cdk5, of WORDS: KEY Cdk5. development of deregulation the by triggered are for that interventions therapeutic strategies to the expected alternative is the regulators at in protein provide Cdk5 these regulation of of modulation roles Specific its pathological brain. and and physiological highlight Cdk5 finally We levels. discuss post-translational of and also that post-transcriptional We activity transcriptional, Cdk5 brains. diseased autoregulatory of several and normal inhibitors the including in and activity regulation, its activators control Cdk5 protein is of identified covers activity recently Commentary mechanisms This Cdk5 various functions. to over physiological the leads its control for which essential precise disease, disease, Alzheimer’s Therefore, Huntington’s as neurotoxicity. and neuronal such disease disorders, numerous Parkinson’s neurological for learning several essential as in deregulated such is becomes activity Cdk5 functions However, it formation. memory cognitive and brain, higher adult including processes, the in development and, brain for indispensable cyclin- is system. Cdk5 the nervous embryogenesis, central During of the in member role pivotal family a plays kinases, a dependent (Cdk5), kinase-5 dependent Cyclin ABSTRACT aoaoyo oeua ergntc,Dprmnso scityadof and USA. Psychiatry 47907, of IN Departments Lafayette, Neurogenetics, West Molecular Drive, of Oval Laboratory 560 Chemistry, of Department 04 ulse yTeCmayo ilgssLd|Junlo elSine(04 2,29–40doi:10.1242/jcs.147553 2391–2400 127, (2014) Science Cell of Journal | Ltd Biologists of Company The by Published 2014. h is ua d a lndi 97b sn functional using by 1987 in cloned was Cdk human first The 1, n eoo .Lahiri K. Debomoy and * b Ayod xiooiiy Cdk, Excitotoxicity, -Amyloid, 2 ioi ern,laigt eldah(hn ta. 2012). al., et (Chang death cell post- in to activate deregulated is leading aberrantly it neurons, can when cycle mitotic but cycle cell post- is cell of cells, in components active. in participate various proliferating Cdk5 not or does vital in expressed Cdk5 2001). not Cdks, progression are other are Tsai, to Cdks functions contrast other In and its where neurons, but (Dhavan mitotic expressed, member ubiquitously PSSALRE family 1992), Cdk 1992). al., al., et (Xiong et Cdk5 and 1992), 1992) (Lew al., al., al., et et et kinase (Meyerson (Ishiguro, (Hellmich proline-directed II (nclk) kinase kinase tau brain like i.e. Cdc2 name, each neuronal although different family, 1992), a Cdk it the of gave member study laboratories new independent of a identification five as 1992, the Cdk5 in for reported and way 1020); the ID: paved (Gene Cdk2 Cdk5 and Cdk1 human of ahlgclfntoso d5i h ri htmgtbe might that brain and the physiological in various interventions. Cdk5 therapeutic the in of exploited highlight functions briefly the pathological we levels. at discuss we regulated post-translational Finally, are addition, and p35 we In and post-transcriptional Cdk5 brains. its transcriptional, which Commentary, diseased to by mechanisms and binding the normal by this describe in regulated is partners In Cdk5 protein which (Hisanaga 2010). through implications mechanisms Endo, multiple clinical activation non- different own and treat and its with neuronal employs in tissues to functions it diverse neuronal that widely in target has Cdk5 Cdks and Thus, strategies, the clinical 2012). among Ip, unique is potential and is Cdk5 (Cheung cancer, a diseases of neurodegenerative types as many several in emerging occurs in commonly of deregulated deregulation Cdks which the other (HD), be although Consequently, disease neurotoxicity. to Huntington’s causes and known (PD) disease (AD), is disease Parkinson’s Alzheimer’s Cdk5 including diseases, Pareek 2006). neurodegenerative 2002; al., al., et Fischer 2001; brain et long-term al., During and et (Bibb addiction and brains changes normal drug learning behavioral adult signaling, cells. plasticity, pain in synaptic for formation, survival, – memory neuronal non-neuronal whereas regulates indispensable 1996), it al., – and et is (Ohshima development neuronal Cdk5 embryogenesis, in functions Cdks. 1995). of regulation the al., in that, roles respectively) crucial p27Kip1, et have and thus, p21Cip1 Tang as to CDKN1B referred binding 1994; and (hereafter regulated CDKN1A inhibitors not kinase al., specific is cyclin-dependent the Cdk5 by members, its et family other (Tsai and requires unlike Furthermore, p35 as respectively) also to referred p39, (hereafter Cdk5 CDK5R2 and activation CDK5R1 partners its For 2,rsetvl)(i.1.Rcn idnshv further have (Brinkkoetter findings specific Cdk5 and of it activator Recent p25 an binding products, as (CCNI) 1). cleaved by I (Fig. cyclin their identified activated (and respectively) is p39 p29, and Cdk5 p35 above, activators partners noted protein by As activity Cdk5 of Regulation d5 lhuhhgl oooost t eaie,i unique a is relatives, its to homologous highly although Cdk5, cuuaigeiec a eeldapehr fCdk5 of plethora a revealed has evidence Accumulating 2391

Journal of Cell Science eanp5i h yols Aaae l,21) osqety a Consequently, 2012). al., et (Asada cytoplasm to the needed in p35 are retain studies further mechanism. However, (PP2A) by possible 2A 2007). this brain phosphatase confirm al., adult protein et in or phosphorylated (PP1) (Kamei T138 1 of are phosphatase dephosphorylation protein sites be increased to in both believed to are undetectable levels due Because phosphorylation and differential the 2). Cdk5, brains (Fig. by fetal brains in T138 whereas adult highest development, during is constant remains phosphorylation two phosphorylation S8 respectively), The of 2007). residues level have al., T138, and et acid (Kamei and regulated consequences differentially different S8 amino are that (hereafter at events by phosphorylation Thr138 p35 or and 2005). mutant, phosphorylates al., Ser8 et Cdk5 primarily (Wei Roscovitine kinase-dead inhibitor Cdk5 Cdk5 or the expression with in by dominant-negative treatment inhibited observed be a is can which of p35 Cdk5, of express that degradation neurons Rapid p35. phosphorylating proteosome. the by degraded rapidly 3 a h is d5atvtrt eietfe Fg ) tforms It 1). (Fig. identified be to activator Cdk5 first the was p35 p35 1). (Fig. 2011) (GSTP1) P al., S-transferase al., et glutathione et (Sun (Modi and (CCND1) (CCNE) D1 E Cdk cyclin cyclin by other 2012), inhibited activate activator. is to Cdk5-specific Cdk5 known a contrast, not be In might is it I suggesting Cyclin members, 1). family (Fig. 2009) al., et COMMENTARY ifrnilyrgltdtruhpopoyaino 1,wihicessisatvt lhuhntb y1adWe,btb p,Alo y.Genar Green als Fyn. is or Cdk5 Abl it. Eph, inhibit by E 2392 but activ cyclin indicate Wee1, or ovals and Green D1 Myt1 phosphorylation. cyclin post-mitotic by through proteins. (in GSTP1, regulation not inhibiting negative Cdk5 whereas although indicate indicate of Cdk5, – arrows boxes Regulators activate activity dashed or (Right) can red its activity, ovals respectively. a I) increases Cdk p21Cip1 Y15, cyclin of which e.g. and regulation or Y15, (CKIs), positive T14 p29 of indicate inhibitors residues p39, phosphorylation Cdk-dependent acid p25, through by amino p35, regulated inhibited of (e.g. differentially and phosphorylation partners I) by binding cyclin Cdks Specific not inhibit neurons). members. (but kinases family cyclins Wee1 Cdk classic other and by of Myt1 activated that are from kinases differs cyclin-dependent Cdk5 these of Regulation 1. Fig. (t half-life Consequently, short a pathway. only degradation membrane p35 ubiquitin-proteosome has for the signal p35 the a for contains important also through p10 is p35. that contains of p10 targeting region Notably, p10. of myristoylated absence leads the the Cdk5 in to even p25 activation C- of its a binding to The and p25. component containing p10 region the terminal encompassing ternary region N-terminal a an cyclin adopt 2001). and al., to Cdk2 et between shown complex (Tarricone the (Cdk2–cyclin-A) fact, been to In A similar 1997). has is al., et that complex (Tang structure cyclins Cdk5–p35 of that domain from the sequence fold distinct primary cyclin-box the is although p35 the activation, of to Cdk for similar required is is that that structure tertiary a d5mdae hshrlto fp5a 8i eurdto required is S8 at p35 of phosphorylation Cdk5-mediated directly by activity its autoinhibits also Cdk5 Active 3 sammrn-nhrdpoenta opie w parts, two comprises that protein membrane-anchored a is p35 rlfrtn el Post-mitoticneurons Proliferating cells p27Kip1 p21Cip1 CKIs Cyclin Cdk7 1/2 5 03 iue)adis and minutes) 20–30 P T161 Cdk Wee P T14 P Y15 Myt Cyclin D1 Lf)Rgltr fCkfml ebr te hnCk.I rlfrtn cells, proliferating In Cdk5. than other members family Cdk of Regulators (Left) hshrlto,wihi unalw cieCk to Cdk5 active allows cells. the turn in direct activity own through in its p35 regulate regulates spatiotemporally of which Cdk5 localization subcellular that phosphorylation, and demonstrate stability activity. own findings its the its autoregulate regulating these to preventing Cdk5 tightly Collectively, allows increases thereby thereby turn, it in p35, MTs, This, Third, levels. and 2). of to (Fig. Cdk5 degradation binding outgrowth proteosomal from neurite its and it inhibits of bundling removes MT phosphorylation T138 MTs Cdk5-mediated 2008) at inactive. to al., p35 kinase et p35 the (He of renders bundling Binding N- MT its through 2). promotes MTs (Fig. binds and cell al., the domain in et p35 terminal (He of T138 amount activity large at Cdk5 polymerization A p35 2008). (MT) of when microtubule phosphorylation Second, its neurotoxicity 2). inhibits (Fig. against highly high is is protect T138 activity formation employ might to p25 brains fetal As phosphorylation below), formation development. discussed the (as brain preventing neurotoxic thereby during calpain, of p25 by cleavage p25 of intramolecular and the p10 prevents to p35 it First, functions. three 2). the (Fig. in 2012) accumulates al., mutant et (Asada S8A nucleus p35 phosphoresistant distribution, a cytoplasmic whereas shows mutant S8E p35 phosphomimetic 03.Ntby hs ertxcislsdsutteintracellular the Rosenmann, 2014; disrupt al., insults are et Ca neurotoxic Perez 2003; which these 2014; al., Notably, of al., et 2013). all et (Lahiri stress, Lahiri AD 2011; oxidative in Lahiri, interventions by therapeutic as for well targeted as neurofibrillary (NFT), as tau tangles hyperphosphorylated of and to A plaques important of neuritic is accumulation by it characterized context, is this AD In that 2006). mention al., et Sahlgren amyloid 1999; al., to et exposure a as under (A p35 such from peptide conditions, generated is neurotoxic p25 of 1). variety Fig. 1994; of al., activator neuron-specific et a (Lew also Cdk5 is p35, of form truncated the p25, p10 and p25 iial,clattn nedgnu niio fclan,is to lead calpains, could which of 2003), 1993). (Nixon, inhibitor AD al., in endogenous et decreased (Saito substantially an AD al., calpastatin, in et activated Similarly, (Lee abnormally p10 are and – particularly p25 – m-calpain calpains into finding, this p35 with agreement cleaves In 2000). turn in which calpain, Cyclin E motnl,popoyaino 3 tT3 yCk has Cdk5 by T138 at p35 of phosphorylation Importantly, 2+ oesai nnuos hrb rmtn ciainof activation promoting thereby neurons, in homeostasis Cyclin I ora fCl cec 21)17 3120 doi:10.1242/jcs.147553 2391–2400 127, (2014) Science Cell of Journal b GSTP1 p35 ,ecttxct,icei n xdtv tes(Patrick stress oxidative and ischemia excitotoxicity, ), Cdk5 p25 p39 P Abl p29 Y15 Fyn EphA tn rtis red proteins, ating b dp27Kip1. nd etd as peptide m o -and rows b

Journal of Cell Science uclua itiuin hra h d5p5complex Cdk5–p35 distinct the and Whereas overlapping distribution. both display subcellular complexes Cdk5–p25 complex Cdk5–p25 the neuronal p35, to leading toxicity. with targets physiological compared its to hyperphosphorylates p25 in prolonged the known to NFs of owing Thus, of are half-life 2004). al., phosphorylation et Cdk5–p25 (Shea aberrant neurons or and diseased to deregulated CaMK2 contribute including hyperphosphorylated MAPK, substantially kinases Several PKA, are bodies. GSK3B, cell they in while several aggregate outgrowth in disorders, However, neurite 2004). al., and neurological et (Shea support the transport in axonal axonal reducing neurofilaments in of Lys-Ser- assembly resulting on the axon, domain promotes AD. tail This its motifs. in at Pro phosphorylates tangles (NF-H) Cdk5 chain neurofibrillary heavy conditions, neurofilament form physiological hyperphosphorylates to under Likewise, aggregates Cdk5–p25 which Cdk5–p35, conditions, is tau, that by However, neurotoxic manner 2003). al., not region-specific under et a (Takahashi but axons, development in developing during Cdk5–p39, growth regulated in neuritic by example, in phosphorylated For resulting cells. is the to tau which to leading targets, it detrimental physiological Cdk5, 1999), is normal al., of its et period (Patrick of activation and hyperphosphorylation p35 the than proteolysis extends half-life ubiquitin-mediated substantially longer to fivefold a resistant has is p25 because Ptro ta. 00.Terltv aayi ciiiso h Cdk5– complexes the Cdk5–p25 activities of and activities comparable p35 catalytic relative reported The have 2010). al., studies et (Peterson other between that p35, than and activity higher Cdk5 a displays p25 and Cdk5 between COMMENTARY eeuaino d5truhicesdfraino 2 (Sato p25 of formation 2011). increased al., through et Cdk5 of deregulation (p35 phosphorylationat T138) Fetal brain (p35 phosphorylationatS8) Fetal andadultbrain (p35 notphosphorylatedat T138) Adult brain eetsuishv ute ihihe htCk–3 and Cdk5–p35 that highlighted further have studies Recent lhuhafew a Although Cdk5 Cdk5 T138 P P T138 Dephosphorylation nvitro in PP2A PP1 or ? tde aesonta h complex the that shown have studies nvivo in Cdk5 S8 Cdk5 Cdk5 P r o nw.Nevertheless, known. not are T138 p35 P Calpain Calpain p35isstable ii iii i Cdk5 of Cdk5–p35 retention Cytoplasmic p25 Cdk5 turnover Rapid p35 MT bundling Neurotoxicity p35 away sequestering MT bundling, from Cdk5 oee,p0de owtotayascainwt h Cdk5–p25 the with More toxicity; association any Cdk5–p25-induced without p25 Cdk5–p25. to so from the does neurons p10 (without specificity with however, protect alone substrate can p10 compared domain) of distinct expression complex a ectopic interestingly, and imparts Cdk5–p35 toxicity p10 the Cdk5–p25-mediated that in suggest p10 results of by domain that loss the neurodegeneration Indeed, degraded for p10 neurons. showed essential rapidly in is the Cdk5–p35 study is that of domain functions it recent pro-survival physiological unique as a a function, possesses However, no have ubiquitylation. to assumed targets targets. physiological non-physiological its of 2012). phosphorylation neurotoxicity, of al., and cause hyperphosphorylation et to Chang believed through is 2011; both complex al., Cdk5–p25 et the of Cdc25A, (Chang Thus, promotes phosphorylating dispersion Cdc25C by and and cycle triggers lamins, cell Cdc25B the phosphorylating Cdk5–p25 of by activation 2008b). aberrant envelop al., al., nuclear et et the (Sun al., peroxiredoxins Sun et promotes phosphorylating Sun 2008a; and by 2008a; GM130 stress al., aberrant phosphorylating causes oxidative et by complex Sun Cdk5-p25 fragmentation The 2012; and 2009). Golgi al., al., Cdc25B et et Chang Sun Chang Cdc25A, 2010; 2008b; Cdk5– 2011; al., 1, B1, et al., peroxiredoxin (Chang of lamin et GM130, neurotoxicity e.g. causes A, access which targets, lamin Cdc25C, new For the 2, of neurotoxicity. another variety allows peroxiredoxin be a Cdk5-induced to mislocalization to to p25 considered the leads is nucleus that example, the factor and complex crucial cytosolic Cdk5–p25 cytoplasm largely the the of is plasma 2006; mislocalization to complex the al., the Cdk5–p25 Thus, et the nuclear. at (Fu and 2008), nucleus and al., the et region in Asada distribution perinuclear less the with membrane to localizes mainly neetnl,p0 h te laaepouto 3,was p35, of product cleavage other the p10, Interestingly, ora fCl cec 21)17 3120 doi:10.1242/jcs.147553 2391–2400 127, (2014) Science Cell of Journal hshrltda 18hsahl-ielne hnits than T138. longer at half-life not counterpart a p35 phosphorylated Moreover, has activity. T138 p35 its at sequesters reducing phosphorylated also thereby It Cdk5, outgrowth. from neurite to away to leading (MTs), and microtubules bundling to their not binds p35 T138 Furthermore, formation at the Cdk5–p25. phosphorylated to complex leads neurotoxic then the which of p25, and calpain-mediated (regardless p10 to T138 yielding susceptible cleavage, at is phosphorylated phosphorylation) not S8 is of that p35 by PP2A. dephosphorylated or anymore, becomes PP1 detected residue not this is because adult T138 presumably In at (Bottom) phosphorylation activity. p35 Cdk5 p35 brain, of reducing degradation thereby of increased, level in to is The p35 outgrowth (iii) prevented. of neurite thereby, ability and is, the neurons bundling of MT Inhibition prevented p35-induced thereby, (ii) MTs. Cdk5. is, bind of neurotoxicity activity brain, high fetal a In despite p25. cleavage to calpain-mediated p35 three of of has Inhibition This (i) p35 Cdk5. consequences: of through known levels mediated high T138 has at the brain phosphorylated of Fetal localization (Middle) cytoplasmic complex. acid a Cdk5–p35 amino promotes at Cdk5 which by S8, phosphorylated residue is p35 brains phosporylation. adult Cdk5-mediated stability and fetal to and response localization in subcellular p35 the of of Regulation 2. Fig. nvivo in Zage l,21) hs findings These 2012). al., et (Zhang Tp In (Top) 2393

Journal of Cell Science oaiaino h ifrn d5atvtrcmlxsis complexes Cdk5-activator Cdk5. not) of subcellular different activity the or kinase that the the phosphorylated by suggest determined is results of These S8 2012). localization whether Cdk5 al., of et p35. addition, phosphorylation (Asada (regardless by through in Cdk5 T84 shared In accumulate by to not inhibited of tendency is analyzed. site higher which a nucleus, unique has the been p39 a p35, T84, with not Compared regulates at phosphorylation has p39 for direct this phosphorylates Likewise, T138 stability whether to by 2012). however, (equivalent al., p39 Cdk5 p39 S173 2); et Fig. at p35, of (Asada p39 p35; to S8 phosphorylates retention also at Similar Cdk5 cytoplasmic p39 2007). of the Cdk5– al., phosphorylation the regulates et destabilizes (Yamada also Cdk5–p35 also complex stabilize has p39 It can Cdk5–p39 2001). that The reconstitute al., is detergent et to complex. it (Ko challenging when membrane Cdk5–p39 abolished cell proven active instantly the is from an Cdk5–p39 extracted of Cdk5–p35; isolate activity known to the catalytic is difficult of little been that Cdk5–p39 signaling, of activity Cdk5–p35 to the about with specificity compared substrate however, and activity uklna h elprpeyi seta o t physiological its for essential is periphery actin complexes cell function. along protein the of recruitment at motor receptor p39-mediated that muskelin different suggesting GABA 2011), Muskelin al., through et the 2005). (Heisler networks of al., MT transport et and adhesion facilitates (Ledee cell regulates organization also muskelin, it where protein cytoskeletal periphery intracellular cell and the the is binds to that which it – a recruiting – 329–366 contains acids p35) (amino p39 in C-terminus under absent 2002). the p29 al., Tsai, and at et p10 insertion and yield small (Minegishi to (Patzke p35 calpain conditions by than cleaved neurotoxic half-life also is longer p39 a 2010). has p39 although brain. the in activators Cdk5 main euti n paetanraiis oee,p5adp39 and that p35 to identical However, is Cdk5 that of abnormalities. phenotype a not apparent display does mice double-knockout deficiency any p39 in whereas brain 1996), result several al., in et defects (Ohshima extensive regions with lethality perinatal display 3 sa sfr fp5adaohrnuo-pcfcatvtrof activator neuron-specific another and p35 of isoform an is p39 p29 and p39 interventions developing pro- pathways. for signaling the Cdk5-mediated well future deregulated Notably, augurs against mechanism. but p10 this of unravel function neurotoxicity, survival to needed Cdk5–p25-mediated are studies inhibiting in with work factors p10 cellular other that suggests finding This complex. COMMENTARY ta.rpre htcci 2mdltsteatvt fthe of activity the modulates D2 2394 cyclin that Guidato its reported However, on 1994). al. al., influence et no Bates et have 1992; al., but et fibroblasts, (Xiong with activity associate diploid D3 human cyclin in and D1 Cdk5 cyclin that showed studies Initial D Cyclin Cdk5 functions. unique several with has overlap also largely it p39 studies p35, of Genetic of functions 2003). those although al., al., that, et et Takahashi shown (Zheng 2003; have cortex al., cerebral et postnatal Jeong the 1998; and of brains, and cortex embryonic hind cerebral in adult the expressed prominently in is expressed p39 highly brains, developing is that from p35 distinct is Whereas expression p35. p39 of of pattern the but 1), (Fig. Cdk5 nvitro In site, myristoylation N-terminal a possesses p39 p35, to Similar 2 / 2 h d5p9cmlxdsly iia enzymatic similar a displays complex Cdk5–p39 the , ie(oe l,20) ihihigp5adp9a the as p39 and p35 highlighting 2001), al., et (Ko mice nvivo in rsmbybcuei has it because presumably , nvitro in 2 sthe as , / 2 mice Fg ) eetwr noee oefrcci 2a a as 2014). al., D2 et a cyclin (Yamak for proteins for be paradigm D role a cyclin might suggests of a Cdk5 effects and it uncovered cell-specific GATA4 of of work E, coactivator inhibitor recent cardiogenic cyclin A relevant to 1). pathologically (Fig. similar or that A physiologically in to Cyclin suggesting exposure particularly 2004). upon upregulated brain, 2012), al., further et mouse Cdk5 be Falco can adult is to D1 (De D1 in neurons cyclin binding pyramidal levels Cdk5–p35 D2, hippocampal cyclin high p35 modulates unlike at with Importantly, D1 expressed 2012). competing al., cyclin et by (Modi a that agreement, possibly In revealed 1998). activity, not al., study et was (Guidato mechanism recent study specific this in the investigated although complex, Cdk5–p35 01.Mroe,cci--eitdsqetrn fCdk5 of al., et sequestering (Odajima p39 cyclin-E-mediated and p35 it Moreover, activators sequesters and normal 2011). Cdk5 its inactivates activating with E from of complex cyclin away instead of a Interestingly, binding forms 2011). the it Cdk5, al., where et also brain (Odajima is E adult Cdk5 cyclin in synthesis that shown DNA expressed have and studies highly cycle Recent cell 1993). the al., et of (Tsai transition G1/S complex E for Cdk2-cyclin critical The 1991). is al., et binds (Koff it Cdk2 where activates cells, and proliferating in expressed normally is E Cyclin E Cyclin Tngcie l,20;YoadLbc 01 adne al., or et exist Tandon Cdk5 for 2001; factors Lubec, regulatory and other that Yoo suggesting 2001; AD 2003), al., in p25 et individuals of unaffected (Taniguchi age-matched levels with Tseng reduced groups compared research when slightly 1999; patients several or al., However, unaltered 2003). et reported al., have et (Patrick Cruz disorders 2002; al., neurological deregulation et the is in to neurons leads Cdk5 that neurodegenerative of mechanism in primary the p25 as of regarded formation aberrant The and GSTP1 phenotype certain a in resulting thereby versa. p25), vice or activators p35 other Cdk5 bind as to the Cdk5 (such allow might potential to levels I contributes A cyclin in levels diseases. decrease neurodegenerative of I in see cyclin pool observed to deregulation in interesting different alteration be will to an it whether Likewise, Cdk5 mechanism. this 2009; recruits needed evaluate are to studies either suggesting complex Future specificity. al., substrate Bcl-XL, it binding Cdk5–p35 alters and or substrates I Bcl2 et the of cyclin contrast, transcription (Brinkkoetter that the In induce 2010). BCL2L1) not (Bcl-XL; does al., large as et lymphoma-extra Brinkkoetter known B-cell and B-cell officially proteins (Bcl2) anti-apoptotic 2 the lymphoma of transcription through 2013). al., complex survival and et also (Nagano neurons is Cdk5–cyclin-I progression I cycle cyclin (e.g. cell The that the in reported cells involved study 2009). recent post-mitotic that a However, al., observed in podocytes). noticed et been exists predominantly has (Brinkkoetter further al., activity et mice authors (Nakamura Cdk5 cyclin-I-deficient time the reduced Cdks, in at classic Recently, the investigated of not 1995). any however, was with forebrain; associate function human to its failed from I isolated cyclin initially because was I Cyclin I Cyclin 1). memory (Fig. relevant physiologically and is cyclin-E- Cdk5 that of plasticity suggesting inhibition models, mediated synaptic animal transgenic in growth, formation dendritic promotes nps-ioi el,teCk–ylnIcmlxidcscell induces complex Cdk5–cyclin-I the cells, post-mitotic In ora fCl cec 21)17 3120 doi:10.1242/jcs.147553 2391–2400 127, (2014) Science Cell of Journal b Md tal., et (Modi

Journal of Cell Science seilyhg eesi h ri Braee l,19) GSTP1 a with 1994). al., is expressed, et (Berhane GSTP1 widely the brain 1). the using is Fig. in by levels GSTP1 2011; high radicals especially motif. al., free glutathione et eliminates reduced (Sun that cell cancer brains enzyme the lines, detoxifying cell AD neuronal for in and Cdk5 lines of regulator mechanisms a is (GSTP1) molecular alternative Cdk5. are of deregulation there that COMMENTARY inln edn op5tasrpini oslro ganglia; root dorsal in transcription Erk1/2 p35 activates to also engagement leading Fas 3). signaling response (Fig. growth (EGR1) early as 1 factor MAP to transcription protein the through referred of expression regulated hereafter participation gene MAPK3, the p35 upregulate extracellular and which (MAPK1 signaling, activate 2 Erk1/2) and factors 1 kinases These factor necrosis 1998). tumor 2004), (TNF al., alpha et (Chen D3 (Lee interferon dihydroxyvitamin acid brain-derived retinoic 2004), 2008), 2001), Kim, al., al., including and et (Lim et stimuli, (BDNF) (Harada several factor (NGF) neurotrophic by factor promoted growth is nerve p35 of Transcription p35 of regulation Transcriptional regulation different Transcriptional in a activity is its 2011). GSTP1 inhibits al., in that et that as (Sun suggesting well Cdk5 tissues brains, as of cancers, AD regulator various and common in lines Cdk5 cell of Most neuronal GSTP1 activity activity. between the Cdk5 correlation and inverse of levels an activator observed potent we associated a importantly, Cdk5 molecules stress, of scavenges for oxidative p25 GSTP1 activity with and Second, p35 the with binding. inhibits competes Cdk5 it GSTP1 First, 1998). mechanisms. that al., two through et revealed (Lovell study AD oxidative that in promotes Our suggesting neurodegeneration that neurons, causes trigger and AD a stress as in acts reduced downregulation are GSTP1 levels and activity eety ehv hw htguahoeStaseaeP glutathione-S-transferase that shown have we Recently, a Urrse l,20)adlmnn(aln tal., et (Paglini laminin and 2009) al., et (Utreras ) c IN)(oge l,20) 1,25- 2005), al., et (Song (IFNG) rmtricesn 3 xrsin(hn ta. 2006). al., et of (Chang cortex p35 expression cerebral the to the binds p35 Hsf2 Accordingly, factor increasing shock heat addition, promoter In 3). and p35 (Fig. of migratingp39 transcription the in regulate factors mRNAs transcription indicating p39 these strongly that and thereby hippocampus, p35 and cortex lack the of mice neurons These 2002). al., (McEvilly defects et lamination cortical severe to exhibit of mice Similar deficient expression p39. gene the and in p35 participate also respectively) 3). POU3F2, (Fig. whether 2007) known al., post- not et or (Bogush is transcriptional level at It is translational striatal 3). levels p35 in (Fig. in levels 2007) increase P13K-mediated al., protein phosphoinositide-3 et p35 the (Bogush increase as neurons to well pathway as (PI3K) transcription, kinase 2009) pathway p35 al., Erk1/2–EGR1 the increase et stimulates (Utreras to BDNF p35 contrast, of In transcription 3). the (Fig. NF- inhibit and which of (JNK) all kinase N-terminal Jun (MAPK14), TNF transcription, p35 increases known not is 2003). upregulation al., EGR1 et to due (Desbarats is this whether however, hti ossetwt 3 eiiny(hn ta. 2006). al., et (Chang deficiency phenotype p35 a with consistent layers, is superficial that within neurons of mispositioning r1 ee d5drcl hshrltsMK MPK)–the of – activation (MAP2K1) MEK1 downregulates phosphorylates directly that Cdk5 Here, mechanism Erk1. feedback p35 of a expression gene though the inhibits also Cdk5 Interestingly, 2004). cAMP- induces and retinoic-acid- of prevents Fos expression Erk1/2 induced of 2004) factors inhibition Kim, Accordingly, transcription and 4). (Lee (Fig. the (CREB) protein binding by element responsive mediated is but of Expression of regulation Transcriptional h rncito atr r- n r- PUF and (POU3F3 Brn-2 and Brn-1 factors transcription The which pathway, Erk1/2–EGR1 the stimulating from Apart ora fCl cec 21)17 3120 doi:10.1242/jcs.147553 2391–2400 127, (2014) Science Cell of Journal eiocai eetr D,vtmnD eetr X,retinoid RXR, receptor; D3 receptor. vitamin X RAR, VDR, post-transcriptionally. receptor; p35 acid of retinoic expression the the through NF inhibit and it 107 JNK inhibits p38, but the pathway, of Erk1/2 activation the this through TNF whether p35 level. unclear protein of or is mRNA it at although mediated to protein, is leading p35 pathway of Erk1/2 PI3K levels the the increased to activates this addition also whether In BDNF unknown EGR1. pathway, is of it upregulation but through pathway, occurs of Erk1/2 transcription the the through increases transcription p35 also the engagement through FasL p35 EGR1. of factor transcription the TNF upregulate and which (D3) D3 1,25-dihydroxyvitamin (RA), interferon- NGF, p35. 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Journal of Cell Science s n lcrcnusv ezrs(C)truhtetranscription the through cocaine (ECS) factor chronic seizures to electroconvulsive response and in enhanced use also is expression Cdk5 Moreover, hshrlto fCE,wih ntr,rslsi t idn otecAMP the to binding its the in at results (CRE) turn, element in response which, CREB, of phosphorylation Cdk5 peuaino h rncitoa atr o n u;te hnbn othe to bind then they the Jun; within and site Fos to AP-1-binding factors leads transcriptional activity the ERK1/2 of of upregulation increase RA-mediated (1) mechanisms: COMMENTARY 2396 Cdk5 for obligatory phosphorylation by is tweaked S-nitrosylation. further partner be or can protein activity a its activation, to binding Although Cdk5 of regulation Post-translational physiological under by both activity conditions. Cdk5 as important pathological of Cdk5 be and such regulation of might the miRNAs, miRNAs activation Thus, specific and 2013). 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Ser159 1). al., corresponding at corresponding (Fig. phosphorylated et the is Cdk2) (Poon Cdk5 phosphorylate Cdk5 whether of to in activation residue unable Ser159 200-fold is strongly a Cdk7 which Cdk1, However, (e.g. in Thr161 them and the Cdk2 in Cdks activates in phosphorylate Thr160 to e.g. known loop, is Cdk7 T latter. the on Cdk7 of 2011). al., et al., Cancino can et 2007; (Lin Tyr15 2002; neurodegeneration in of al., resulting phosphorylation Cdk5, et hyperactivate Abl-mediated also Sasaki 2003). al., 2000; et al., (EphA) activation Cheng et its A (Zukerberg outgrowth to synaptogenesis neurite to receptor migration, leading and neuronal Tyr15, ephrin promoting unable thereby at 1), Abl, are Cdk5 (Fig. kinases phosphorylate kinases Fyn the these and 1997) Instead, however, Booher, and 1). (Fattaey Cdk1; (Fig. position family either Tyr15 of at and its Cdk5 case Thr14 phosphorylate of example, the for other that of at, in activity from phosphorylation the dual inhibit differs by Myt Cdks and activation But Wee1 Ser159. kinases Cdk5 The and members. of are Tyr15 Thr14, mode that family: sites the Cdk phosphorylation the among conserved common three possesses Cdk5 Phosphorylation ihihsangtv oeo d5i erigadmemory and learning in Cdk5 of which role tasks, negative learning a enhanced behavioral highlights in hippocampal results in improved mice performance and plasticity knockout synaptic conditional NMDA-receptor-mediated LTP, Cdk5 in hippocampus plasticity Cdk5 synaptic the and of function 2011). neurons al., memory et pyramidal (Guan impaired CA1 revealed the – al., selectively and is in Cdk5 et stress which ablated in to (Fischer – is mice exposed conditioning Cdk5f/f/T29 Cdk5 Similarly, are 2002). fear Likewise, that context-dependent 2005). long-term mice facilitates al., of in induction upregulated et long-term defective transiently (Ohshima of the (LTD) erasure and the depression – – (LTP) depotentiation p35 potentiation display in identified role which was positive plasticity A mice, synaptic memory. promoting of in formation Cdk5 the of and learning in roles Cdk5 contrasting of revealed have models animal transgenic Notably, plasticity synaptic and Cdk5 brain the in Cdk5 the in transnitrosylase. enhanced nascent is a Cdk5 as A of acts of presence higher also S-nitrosylation has only but not Importantly, Cdk5 activity S-nitrosylated Thus, spines kinase 2011). dendritic al., in et fission mitochondrial (Qu fission to In mitochondrial leading the 2010). Drp1, transnitrosylates protein they synthase al., turn oxide et whereas in nitric (Zhang which neuronal 2011), (NOS1), by mM) al., S-nitrosylated (1 is et concentration Cdk5 neurons, (Qu high at Cdk5 it of inhibit activity (200 the concentration low augment at agents S- nitrosylating with Interestingly, treated when S-nitrosoglutathione Cys157 or and nitrosocysteine Cys83 at S-nitrosylated is Cdk5 2001). al., et S-Nitrosylation (Tarricone activity its inhibits site this at 01 ue l,21) ugsigta eeuae d5also Cdk5 deregulated reactions conditions. 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Journal of Cell Science niiosmgtpeetA prevent might inhibitors u locutrcscagsidcdb T n T to LTD a and as functioning LTP thereby by stability, induced network together, (NR2B), changes LTD, neuronal Taken and 2B counteracts maintain LTP 2008). promotes also only subtype al., not but Cdk5 et calpain-mediated receptor that imply (Sato findings tau-tubulin expedite NMDA these deficits which learning the Likewise, activity, causing of mice, Cdk5 2007). degradation elevated transgenic al., display (TTBK1)-overexpressing et kinase-1 (Hawasli formation COMMENTARY reesbesmtm fP.Ck loidcsatpayi the in autophagy induces destroys also causing Cdk5 treatment brain, PD. to the of MPTP of symptoms nigra leading 2003). irreversible substantia the al., neurons, in neurons et dopaminergic dopaminergic (Smith in death of complex neuronal levels Cdk5–p25 higher in the results (MPTP)-treatment tetrahydropyridine 2007). al., et Glicksman 2004; (Monaco, patients AD in loss synaptic to leading BACE1, A of of overexpression transcription aberrant that Cdk5-mediated showed further show increases al. et p25 formation Wen p25 NFT 2003). al., and tetracycline-inducible et dysfunction (Cruz synaptic 2010). express cycle atrophy, al., brain cell that et substantial (Lopes aberrant mice loss hyperphosphorylation, neuronal Transgenic and tau synaptotoxicity causes induction, the and of injection p25, intracerebroventricular al., model, et mouse A (Lee a individuals In non-demented of brains 1999). with in compared observed been patients has AD Cdk5 of activity higher Significantly diseases neurological in Cdk5 the of upregulation persistent by of factor regions dopamine exposure transcription chronic brain potentiates of contrast, levels associated In which mRNA 2000). upregulates T34, al., cocaine et PKA. residue (Nishi activates signaling at 1B which subunit regulatory levels, (DARPP-32) 1 phosphatase dose dopamine protein phosphorylates acute by increases PKA An striatum terminals. cocaine the axon of at in re-uptake levels dopamine dopamine inhibiting synaptic enhances Cocaine addiction drug and Cdk5 2007). al., et knockout (Pareek conditional hypoalgesia Cdk5 palpable opposite Similarly, display the mice 2006). has al., et p35 with (Pareek compared of effect overexpression when whereas stimuli mice, thermal wild-type the to hyposensitivity peripheral In pain 2006). display al., mice p35-knockout during et pathway, molecular (Pareek this Cdk5 with p35 agreement of increases hyperactivation of to cleavage leading p25, subsequent further to by are followed expression p35 response, inflammatory and spinal Their Cdk5 and al., ganglion 2007). et trigeminal al., cord. DRG, (Pareek et the rats Yang in and expressed 2007; abundantly mice al., of et Pareek (DRG) 2006; ganglion root dorsal in the pain inflammatory hyperalgesia-associated heat facilitates Cdk5 pain and Cdk5 plasticity. synaptic of regulator homeostatic fetdnuost rcs fctacietrlchanges, cytoarchitectural of process the a addiction. dedicates an to to elicits irreversibly leading thus, neurons of that Cdk5, depotentiation response affected 2001). levels in al., homeostatic protein resulting et adaptive T75 activity, (Bibb. and at signaling PKA phosphorylated activity dopamine of DARPP-32 Cdk5 of inhibition levels and in elevated Increase in results 4). Fig. 2000; b nmuemdl fP,1-methyl-4-phenyl-1,2,3,6- PD, of models mouse In 14)ppiehprciae d5bcueo h omto of formation the of because Cdk5 hyperactivates peptide (1–40) b rcsig(e ta. 08.Teeoe Cdk5 Therefore, 2008). al., et (Wen processing d oB(ibe l,20;Kl n Nestler, and Kelz 2001; al., et (Bibb FosB b n erfbilr ahlg and pathology neurofibrillary and Cdk5 n 3 nreward- in p35 and 00.I h aeo D d5drglto slne ostriatal to linked 2008). is al., deregulation et Cdk5 al., (Paoletti HD, et death of (Menn neuronal case progression the disease In in the 2010). role not and crucial inhibition its but Cdk5 Cdk5 underscoring 2007). between affected al., in link et neuroprotection the confers (Mitsios a in ischemia suggesting of increased pathogenesis neurons, substantially healthy are in p25 and al., et (Anglade 2003). models al., the mouse et PD in PD Zhu and 1997; to patients occurs PD linked both accumulation been of brains has autophagosome autophagy and (Wong of B1 pathogenesis, Deregulation endophilin 2011). of al., phosphorylation et the through model PD enscesu nciia ras ie h ioa oeo d5in Cdk5 not of far role thus pivotal the – Given effect trials. potential, side clinical serious their in to successful despite been owing result, Cdks – a have other several As inhibitors potency. inhibit Cdk5 higher show are they or because concurrently equal there specificity with they and Although inhibitors, selectivity poor Cdk5 functions. multiple is high-potency treat motor Cdk5 known to brain, deficits, defective order memory the and in and learning in involve target Cdk5 that drug disorders of neurological attractive roles an different considered these on target Based drug a as Cdk5 eeta morpi aea ceoi n Niemann-Pick frontotemporal therapeutic and stroke, and sclerosis effective ischemia C. lateral type PD, disease of amyotrophic HD, conditions in AD, dementia, development Cdk5 as of deregulation such the from alternative arise an that provide interventions for which might exist, regulators regulators strategy and these Cdk5 activity Targeting specificity, of substrate levels. more localization, Cdk5 many affect It that might disorders. likely neurological also various alternate in is uncover deregulation might Cdk5 specimens of tissue is modes modulators Whereas diseased I these and cyclin of GSTP1. normal analysis activity, retrospective in and Cdk5 A inhibit Cdk5. I of GSTP1 activator cyclin and an post- E E, cyclin cyclin D1, transcriptional, cyclin Cdk5, D1, of regulators cyclin protein at unknown including far have multiple so studies Cdk5 several identified Recent identified also levels. have regulate post-translational studies and transcriptional emerging that of CNS, regulators predominant mechanisms the the studies as in p39 earlier and Cdk5 Whereas p35 regulators. on focused Cdk5 mainly an of revealed also number but numerous Cdk5, increasing uncovered of only roles not pathological has and years physiological 25 past the over its Research on brake Conclusions a putting while the Cdk5 retain behavior. normal neurotoxic to of allow by the functions would caused compromising physiological approach an pathologies without Such neurodegenerative Cdk5–p25 neurodevelopment. the of expression rescues deregulation mice, CIP CIP-p25-transgenic Cdk5–p25 In of of 2013). 125 and al., a hyperactivation effectively et 2002), (Sundaram (CIP), the al., et peptide inhibits (Zheng inhibitory p25 specifically of to Cdk5 fragment used Likewise, acid be amino (Zhang 2012). potentially neurotoxicity al., can et Cdk5–p25-mediated and cleaved encouraging abrogate (the is p10 selectively p35) of the Cdk5-specific respect, function of this the pro-survival In develop product p35. abrogate the with to not regarding selectively but finding p25 beneficial that with Cdk5 inhibitors be of interaction engineer would or it inhibitors, brain, the nsrk-fetdptet,lvl fpopoyae d5 p35 Cdk5, phosphorylated of levels patients, stroke-affected In ora fCl cec 21)17 3120 doi:10.1242/jcs.147553 2391–2400 127, (2014) Science Cell of Journal nvivo in oeso shmaadstroke, and ischemia of models nvivo in 2397

Journal of Cell Science hn,K . utn,P . u,K . icn,F,d al,Y,Goh S., Ghosh, Y., Pablo, de F., Vincent, H., K. K. Shah, Sun, and S., P. A. Multani, M. H., Smith, K. G., Chang, H. Lee, P., H. Lee, Y., Pablo, de H., K. Chang, Fatimy, El Y., Gitton, M., Rallu, D., Trouillet, M., Akerfelt, P., Ostling, Y., Chang, R. Bernhardi, von M., E. Toledo, U., P. Castro, K., Arce, de Perez I., G. Cancino, rnketr .T,Ppi,J .adSakad .J. S. Shankland, and W. J. Pippin, T., P. Brinkkoetter, eFlo . eee . eLc,L,Pna . otn,G,Cvlot,I., Cavallotti, G., Cottone, R., Penta, L., Luca, De V., Fedele, M., Falco, De Pippin, D., R. Krofft, S., Henderson, S., J. Wu, P., Olivier, T., P. Brinkkoetter, E., Sluzas, Z., Mao, Q., Yang, T., Chan, J., Pelta-Heller, S., Pedrini, A., Bogush, L., G. Snyder, A., Nishi, P., Svenningsson, R., J. Taylor, J., Chen, A., J. Bibb, References after release for PMC in Association Deposited Alzheimer’s D.K.L. the months. to and 12 University Aging, D.K.L., Indiana on and CTSI- Institute K.S. and National to (IIRG) the Health from of support Institutes grant National the appreciate sincerely We Funding interests. competing no declare authors The interests Competing COMMENTARY 2398 H. L. Tsai, and H. Shih, A., J. Goldman, C., H. Tseng, C., J. Cruz, T., Nakayama, Cheung,Z.H.andIp,N.Y. H., Tanaka, Y., Sugiyama, M., Shoji, Y., Sasaki, Q., Cheng, P. G. Studzinski, and X. Wang, Q., Wang, F., Nestler, Chen, and L. Zeng, S., E. Ang, C., Steffen, B., M. Kelz, Y., Zhang, J., K. Chen, Shah, and F. Vincent, H., K. Chang, and Engstro C. M., Dickson, Widersten, A., K., Holder, Berhane, D., Parry, D., MacAllan, L., Bonetta, S., Bates, S. Hisanaga, and T. Saito, A., Asada, S. Hisanaga, and N. Hayashi, T., Saito, M., Gohda, N., Yamamoto, A., Asada, J., Marquez, P., P. Michel, T., M. 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A. protein neuronal Nairn, the by C., regulated C. 410 are Ouimet, cocaine to K., exposure Z. chronic Sagawa, Z., Yan, bratCk ciainb 2 rgesptooia vnslaigto leading events pathological triggers p25 tangles. by neurofibrillary and activation neurodegeneration Cdk5 Aberrant diseases. neurodegenerative cells. ganglion retinal Y. in Neurosci. Goshima, Cell. signaling and ephrin-A5-induced K. mediate Takei, F., Rho-kinase p35 terminal Nakamura, the N., of of Mizuki, onset expression consequent differentiation. increased and cell HL60 5 to of kinase phase contributes cyclin-dependent of D3 activator 1,25-dihydroxyvitamin by [Delta]FosB. of 8971. role seizures: electroconvulsive chronic J. neuronal E. inducing phosphatases and kinases cycle cell death. of activation aberrant human by peroxidation lipid beta-unsaturated and alpha, reactions other radical and transferases. of propenals glutathione products base of aldehyde Detoxication (1994). 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P., Greengard, P., Chambon, 453-459. activity. cdk-5/p35 cellular modulates 70 and cdk-5 with interacts D2 e25735. uklnrgltsatnflmn-admcouuebsdGB()receptor GABA(A) microtubule-based and neurons. filament- in Ba transport actin M., regulates Schweizer, Muskelin J., T. Hausrat, microtubules. on effect its 13252-13260. regulate p35 of phosphorylation iaeAptwy uigrtni-cdmdae ernldfeetainin differentiation protein neuronal mediated and retinoic-acid cells. kinase SK-N-BE(2)C during neuroblastoma extracellular-signal-regulated human pathways the A through kinase p35 muskelin. of activator localization peripheral promotes p39 Chem. activator 5 kinase S. P. base. Print] off not of but Off-site trial: inhibitor BACE1 disease. Alzheimer’s in 97-112. developments drug for strategies ernseii ciao fCk,truhidcino Egr1. of induction through Cdk5, of activator neuron-specific laaeo h D5atvtrp5t 2 yst-pcfcphosphorylation. site-specific by p25 to p35 activator Chem. Biol. CDK5 J. the S. of Hisanaga, cleavage and H. Sorimachi, cerebellum. mouse the in Y. stripes in K. expressed Lee, and filaments. helical paired of 10897-10901. component A68-like into K. protein Imahori, and T. Uchida, M., neuronal death. and survival predominantly neuronal in with activity kinase kinase protein cdc2-related a expression. kinase: like ies brain. disease N. cdc2. gene R. control cycle cell yeast fission the of homologue cnie,L S. L. Schneider, family. gene CDC2 the of members M. J. Roberts, neurodevelopment. during function H. L. 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