hrpuis aeUiest colo eiie e ae,C 06520-8066, CT Haven, New Medicine, of USA. School University Yale Therapeutics, T05086,USA. 06520-8066, CT eerlcvrosmlomto rtisa glance Draheim M. a Kyle at proteins malformation cavernous Cerebral Glance a at Science Cell ß euti nrae iko toe oa erlgcldfcsand defects 1 neurological focal stroke, of risk cavernous increased that cerebral neurovasculature, in the or in result cause by especially malcavernin) vessels, characterized blood CCM3) are and leaky dilated abnormalities OSM as These as (CCMs). known malformations known (also (also known PDCD10 CCM2 (also KRIT1 CCM1), encoding as genes in mutations Loss-of-function ABSTRACT Ato o orsodne([email protected]) correspondence for *Author USA. 06520-8066, CT Haven, eateto hraooy aeUiest colo eiie e Haven, New Medicine, of School University Yale Pharmacology, of Department 04 ulse yTeCmayo ilgssLd|Junlo elSine(04 2,7177doi:10.1242/jcs.138388 701–707 127, (2014) Science Cell of Journal | Ltd Biologists of Company The by Published 2014. 3 eateto elBooy aeUiest colo eiie New Medicine, of School University Yale Biology, Cell of Department 2 nedprmna rga nVsua ilg and Biology Vascular in Program Interdepartmental 1 raaS Fisher S. Oriana , 1 iu .Boggon J. Titus , 1,2 n ai .Calderwood A. David and ppoi.I hsCl cec taGac ril n the understanding. protein–protein current and our known highlighting in and article how phenotypes gaps cellular on Glance to models focusing contribute current might a function interactions of protein at overview CCM an Science of provide we Cell poster, adaptor and this accompanying polarity and basic migration, In of adhesion, cytoskeletal range apoptosis. cell a including signaling, in roles processes of also their cellular for proteins range accounting adaptor presumably a proteins, multi-domain complex, essential with trimeric these a interacts in of exist each can proteins and CCM three The seizures. inln,KI1 CC0 h inln,Vsua biology Vascular Signaling, Rho PCDC10, Cell KRIT1, CCM, signaling, malformations, cavernous Cerebral WORDS: KEY 1,2,3, * 701

Journal of Cell Science aclrcls u eas l he C rtisaewidely vasculature. the are of proteins outside roles CCM have three also all might the they in because of expressed, roles the but light potential review on cells, In primarily we vascular focus signaling. we Here, protein phenotype, disease CCM formation. CCM on CCM of each information to of limited current loss leads is the proteins which still recent the through there these mechanisms determining PDCD10, and the and and of S1) CCM2 knowledge partners KRIT1, Table binding of structures identifying material CCM-knockout in of 2006; supplementary analysis advances al., et extensive (see (Denier Despite disease animals 2011). the al., of often form et mutation severe its Zhu more as might same a CCM2, PDCD10 the and in However, in KRIT1 results from below). found separately be (see act can cell also proteins the all by three within involving bolstered all complex is pathway hypothesis that This essential knowledge 2008). an the al., et is (Stahl proteins Box there (see three 2012) that al., et suggesting (Cavalcanti CCM3) 1), as known also CCM1), 10, death as known also ELSINEA GLANCE A AT SCIENCE CELL 702 genes: CCM for three the treatment of only one the Currently, neurological resection. al., 2013). surgical et focal (Cavalcanti is al., liver and CCM and et skin seizures Fischer the central in stroke, 2012; seen also the for are result they they of risk deficits, where retina), increased neurovasculature cord, are spinal they in brain, the although (i.e. and, system within population nervous been the found of have luminal decreased 0.5% CCMs primarily to and 2013). the up al., lamina in et reported (Tanriover basal in pericytes the Ultra- of junctions), ruptures from numbers lamina. intercellular detachment damaged revealed lack basal to endothelial and due has intact leaky (probably thin, endothelium an analysis are muscle and walls smooth structural vessel no lack support the al., or lesions so sub-endothelial These et little tissue, 2013). elastic Cavalcanti with al., and in et sinusoids (reviewed Fischer packed 2012; parenchyma densely brain form intervening back- arranged to are that to-back of (‘caverns’) clusters channels of endothelial consist enlarged (CCMs) malformations cavernous Cerebral Introduction 03 th ta. 2008). al., Riant et Stahl 2012; of 2013; al., thirds mutations, et identified two with (Cavalcanti and lesions In identified cases 2013). the al., been familial of et one has of least at genes 20 in mutation CCM of lesions, multiple out with cases 19 loss sporadic a the In to leading function. mutations disease-causing in nonsense of of are list al., CCM growing which factors sporadic a et of is most cause Dammann there mutations, other also and 2011; 2009), genes al., but al., CCM et (Limaye et in 2008), mutations (Boulday Local formation al., 2013). a lesion have et in Pagenstecher also role 2013; potentially Stahl CCM could al., microenvironment the 2009; et neurovasculature of Dammann al., copy 2009; wild-type al., et remaining et the (Akers local remove gene a to require to hit appears second development germline Malformation 2012). heterozygous al., a et hemorrhage with in increased with associated mutation 2012), is loss-of-function and CCM al., lesions Familial et rates. multiple (Cavalcanti CCM exhibiting sporadic patients than severe only more for accounts CCM Familial CCM of Genetics The 1. Box n6%o cases, of 65% in Csaeascae ihls-ffnto uain nany in mutations loss-of-function with associated are CCMs CCM2 n1% and 19%, in CCM2 KRIT1 KRIT1 , or , 0 fcssbttnst be to tends but cases of 20% CCM2 PDCD10 PDCD10 Ke neato rpe 1, trapped interaction (Krev or PDCD10 n1%(in tal., et (Riant 16% in KRIT1 porme cell (programmed (Cavalcanti smutated is htrpeet aaimfrhwsalGpoen a idand bind can Rap1 G-proteins GTPase small how small for Recent interaction the paradigm and a of 1997). represents domain mode that al., FERM novel KRIT1 et the a between (Serebriiskii revealed protein analysis crystallographic Rap1-binding domain a FERM as cell 2005). its al., endothelial et through Zawistowski to 2007; junctions localizes al., et also cell–cell (Glading KRIT1 or 2007). boundaries al., et Dufour xrsino E1adDL idctv fNthactivation) Notch of increased (indicative to DLL4 and leads HEY1 overexpression of in expression KRIT1 KRIT1 pathways. discerned. of being signaling still role is and exact in complex activation the is integrin cells Thus, endothelial of regulation 2013). decreased ICAP1-mediated al., to modulating to leads et appears increased loss also (Faurobert consequently KRIT1 KRIT1 ICAP1 and when so levels cells, to protein, ICAP1 endothelial observed bind ICAP1 In to the is 2013). available stabilize al., are activation et KRIT1 (Liu integrin of amounts increased increasing integrin KRIT1, of tail with to cytoplasmic interact the to or motif site b NPxY binding 2013). KRIT1 al., same the et the either (Liu motifs uses NPxY/F ICAP1 KRIT1 three region Importantly, the RR of highly-conserved first the the and regions: two recognizing mode, zebrafish or Rap1 ( in functional either KRIT1-null bind the highlighted to rescue The unable not are is do that HEG1 localization. mutants interactions KRIT1 as junction these studies, protein of a KRIT1 (HEG1), to importance 1 for bind glass of KRIT1 also heart can essential protein of domain conformational anchor FERM membrane localization a KRIT1 the subcellular The is through below). the there microtubules (discussed and that controlling Rap1 suggesting regulation not binds are domains, KRIT1 occurs al., different this but et which (Liu known, by junctions yet mechanisms cell–cell microtubules molecular of The stabilization to 2011). the KRIT1 and KRIT1 of of binding 2012). al., the et (Be Li inhibits 2013; binding al., et Rap1 (Gingras domains FERM recognize h oeo neato sntytcmltl nesod(Be is understood completely loop yet although not domain microtubules, is interaction to Nudix of KRIT1 mode KRIT1 of the targeting a the within for responsible sequence 2005). al., polybasic shuttled et (Zawistowski actively A nucleus is the and and cytoplasm compartments the between observed cellular is different KRIT1 many 2004). in in al., expression et (Guzeloglu-Kayisli endothelial vessels many pronounced large in its expressed with through ubiquitously embryogenesis signal is to early been KRIT1 below). thought has (see activity is partners catalytic it binding No and poster). KRIT1, al., (see for et 2012) reported (Gingras al., domain et moesin) C-terminal Li radixin, a 2013; ezrin, and 4.1, domain (Liu (band ankyrin-repeat motifs predicted FERM NPxY/F a three 2013), of al., stretch et a N-terminal by an followed contains It domain proteins. Nudix CCM the of largest the is KRIT1 KRIT1 proteins CCM yolsi oanascae rti- IA1,a (ICAP1), protein-1 Millon-Fre that regulates associated protein negatively (PTB)-domain-containing binding domain phosphotyrosine cytoplasmic Table material supplementary (see 2011) al., et (Gingras S1). Liu development 2012; cardiovascular al., in et defects with associated .A CP antihbtitgi ciainwe ti bound is it when activation integrin inhibit cannot ICAP1 As 1. RT a ntal dniidi es w-yrdscreen two-hybrid yeast a in identified initially was KRIT1 RT a lobe ikdt eea te important other several to linked been also has KRIT1 nte motn idn ate fKI1i integrin is KRIT1 of partner binding important Another ´ adDfu ta. 07,teeyealn h relocalization the enabling thereby 2007), al., et raud-Dufour ora fCl cec 21)17 0–0 doi:10.1242/jcs.138388 701–707 127, (2014) Science Cell of Journal ´ ilne l,20) CP id RT nabidentate a in KRIT1 binds ICAP1 2008). al., et millon b nernatvto Lue l,2013; al., et (Liu activation integrin 1 santa b hntp,wihis which phenotype, ) nernactivation integrin 1 ´ raud-

Journal of Cell Science irtbl idn sascae ihapeue ‘closed’ presumed a example, with for associated localization; its is regulate binding to FERM thought microtubule the are conformation KRIT1 by the unclear in of still Changes motifs is 2010). interaction Albiges-Rizo, NPxY/F this and (Faurobert of KRIT1 specificity the proteins, the although domain, of FERM ‘head-to- though recognition a occurs other probably the through interaction head–tail conformations like The closed interaction. tail’ and KRIT1, open both that adopts possible therefore ofrainlcagshsntytbe dqaeyexplored. adequately KRIT1 been of yet importance not signaling has and changes is functional conformational The binding 2007). (Be ICAP1 al., conformation and et ‘open’ presumed 2009) a with al., associated et (Francalanci conformation xrsino h ecieoye pce (ROS)-scavenging species oxygen reactive phosphorylation the ERK1/2 of expression increased show phosphorylation, (Wu lesions ERK1/2 CCM increased to and leads the Notch cells and endothelial Consist activation diminishes ERK1/2. (PI3K)/AKT of repression KRIT1 3-kinase phosphoinositol of to silencing (Wu signaling conversely, and, GLANCE A AT SCIENCE CELL nue eldahi erbatm rmedulloblastoma, or neuroblastoma in interaction This death 2009). al., cell et (Harel cells induces nerve on targeting found junctional kinase in motifs domain NPxY/F 2010). PTB cell–cell al., KRIT1 CCM2 et the the (Stockton to of of one interaction (CCM2-F217A) localizes an KRIT1 with bind implicating cannot not, CCM2 that does mutant CCM2- a wild-type is in but junctions, re-expressed it of cells, when that loss Indeed, suggesting the knockdown KRIT1. junctions, by following there cell-cell lost targeted to is localization junctions KRIT1 localization cell–cell been CCM2 endothelial also 2010). the to has Albiges-Rizo, KRIT1 in and complex binding with KRIT1–ICAP1 (Faurobert CCM2 the cytosol interaction of However, sequestration its 2007). in implicated through al., probably et (Zhang nucleus, the of (HHD) poster). (see domain 2013) harmonin-homology al., at domain et the helical (Fisher a termed contain C-terminus to al., shown its et been (Liquori recently N-terminus has by its and CCM2 complex at 2003) 2007a). domain CCM al., PTB et predicted the (Hilder a to proteins of contains addition signaling hub other in 2006; of the PDCD10, number al., and as a KRIT1 acts et both in It (Petit binding including 2006). simultaneously tissues KRIT1, al., multiple et of of Seker that cells to an endothelial and similar activity arterial very enzymatic no pattern with protein expression scaffolding a is CCM2 CCM2 domain FERM its with consequent interact binding and can intramolecular N-terminus harbor localization (Be its to i.e. thought subcellular sites, is its KRIT1 signaling. for that important pathways multiple in death. 2012). involved cell co-expression al., was prevent is et its (Guazzi KRIT1 that expression protein, Collectively, SOD2 suggests supports Nd1 cytoskeleton-stabilizing data KRIT1 of with and actin isoform identified long recently an the interactor, AKT-dependent (Nd1-L), al., KRIT1 et and Another (Goitre inactivation) 2010). state phosphorylation, thus steady (and AKT phosphorylation the FOXO1 ROS, in of increases consequent levels with SOD2 enzyme h ofrainlognzto fKI1apast be to appears KRIT1 of organization conformational The h C2PBdmi lobnsTk,arcpo tyrosine receptor a TrkA, binds also domain PTB CCM2 The out and in shuttle can and cell the throughout found is CCM2 ´ seuee l,21) oso RT lordcsthe reduces also KRIT1 of Loss 2010). al., et ¨stehube adDfu ta. 07 rnaac ta. 09.I is It 2009). al., et Francalanci 2007; al., et raud-Dufour seuee l,21) oc inln slinked is signaling Notch 2010). al., et ¨stehube n ihti,ls fKI1in KRIT1 of loss this, with ent ´ raud-Dufour C2i AKptwy scerycmlx n better a and complex, of clearly study. role is further The require pathways 2009). will understanding MAPK al., not et in (Whitehead does MAPK CCM2 and signaling loss JNK affects (MKK) rather CCM2 but kinase pathway, that the MAPK p38 suggests of the affect might study (PLC) response signaling another C a the Conversely, phospholipase that elicits through indicates stress occur but osmotic pathway, Recent that 2007b). CCM2–RAC1 al., confirms et RAC1-dependent (Hilder linking activity work of p38 to capable 2005). reorganization is al., actin that et complex a Zawistowski organizes 2003; in a F-actin al., ruffles binds p38 et the CCM2 shock membrane in (Uhlik MEKK3 and osmotic cascade to RAC1 scaffold MAPK relocalizes upon to thought CCM2 is and CCM2 where of activation, portion kinase MAPK hyperosmolar- significant for protein required p38 mitogen-activated is It induced the MEKK3. kinase binds kinase pathway (MAPK) it this because whether (OSM) al., and unclear. remains et death, phenotype, between (Costa cell CCM the kinases induces kinase complex to contributes center serine/threonine it germinal a How of the 2012). group of of (GCKIII) member recruitment a III STK25, the and PCDC10 through probably Zege l,21) oso zebrafish of Loss cells 2012). endothelial al., activated in et expressed to (Zheng identity selectively sequence is high that with CCM2 protein a (CCM2L), CCM2-like of hshts P2 n te TIA components STRIPAK protein with other complexes and thus (PP2) and also 2 PDCD10 directly 2010). striatin al., phosphatase et striatin the (Fidalgo kinases where binds GCKIII within complex to (STRIPAK) binds resides kinase it and predominately phosphatase MST4/ al., best interacting et PDCD10 kinases, The (Sugden protein but STK25/YSK1/SOK1 2013). of complex. and explored, group this STK24/MST3 GCKIII dimerization-domain-mediated MASK, being of the involves still with outside these interactions is roles of Its complex has characterized 2007a). CCM also al., the PDCD10 et in heterotrimeric the (Hilder function in component complex third the KRIT1–CCM2–PDCD10 is PDCD10 and 2010), (see 2010) binds al., also et It Ding poster). FAT-H 2011). 2010; al., al., its et et 2007), (through (Dibble Kean phosphotidylinositides striatin 2009; al., al., and et et 2013b) (Goudreault domain) al., (Voss al., et et PTPN13) (Zhang (Li UNC13D as domain) Zhang known FAT-H 2013; protocadherin- (also its al., (through FAP-1 et paxillin Xu 2011), 2013a), 2010; al., al., serine/ including et GCKIII et proteins the (Fidalgo 2007), of al., kinases variety et Voss threonine a 2007a; binds al., It et (Hilder poster). C- CCM2 (see a 2010) and (Li 2010) al., domain al., et (FAT-H) et targeting-homology N-terminal Li adhesion 2011; focal an al., terminal contains et (Kean and domain expressed dimerization ubiquitously is PDCD10 PDCD10 eitdjntoa tblt Zege l,21) Whether determined. 2012). be CCM2- to al., remains blocks disease to et human functionally to binding (Zheng linked and is for stability CCM2L PDCD10, CCM2 junctional not in with mediated overlap CCM2 competes but complete of not CCM2L KRIT1, is overexpression there as by However, rescued functions, 2013). al., partially et be (Rosen can and S1) ccm2 infcn eetavnei h il a h identification the was field the in advance recent significant A MEKK3 for scaffold osmosensing as known also is CCM2 h DD0FTHdmi neat ihCM L tal., et (Li CCM2 with interacts domain FAT-H PDCD10 The nl ( -null ora fCl cec 21)17 0–0 doi:10.1242/jcs.138388 701–707 127, (2014) Science Cell of Journal valentine c Lne l,21) EF H ta. 2010), al., et (He VEGFR 2010), al., et (Lin hntp splmnaymtra Table material (supplementary phenotype ) nvitro in idn sas ugsigta it that suggesting assays, binding c Zo ta. 2011). al., et (Zhou 1 ccm2l hncpe the phenocopies 703

Journal of Cell Science iae rmteSRPKcmlxt h og Ka tal., et GCKIII (Kean of Golgi the binding GCKIII to the complex for shifts STRIPAK a PDCD10 the important from of through kinases is loss complex mutually STRIPAK. as interaction Golgi with interaction localization interaction PDCD10–GCKIII the an PDCD10–GCKIII The of the GOLGA2, PDCD10–GCKIII to face with exclusive Alternatively, cis interaction 2009). the GCKIII PP2 to al., phosphatase localizes to et kinases GCKIII (Goudreault linking thereby indirectly, GLANCE A AT SCIENCE CELL OKihbtr eessti nraeadtesrs fiber stress with the the treatment phosphatase. 704 and increases whereas increase (MLC) PDCD10 MLC, this or chain reverses phosphorylated CCM2 ROCK-inhibitors light of and KRIT1, amount phosphorylating myosin of by Knockdown the which contractility ROCK, kinase inhibiting actomyosin serine/threonine the is increases RhoA effectors primary activated the or of of CCM2- One 2010; this, KRIT1-, cells. with in al., endothelial Consistent increased et PDCD10-deficient 2010). is Stockton al., RhoA 2007; et (GTP-bound) Zheng al., activated RNA- 2009; proteins et al., after CCM Glading et increased 2009; Whitehead RhoA) the al., of of activated et any of observation (Crose of sign the knockdown (a from interference-mediated contribute formation might came fiber dysregulation pathology stress RhoA CCM be that to signaling indication can RhoA–ROCK first in proteins The observations CCM of conflicting role The these determined. How be Zhu to 2013; 2010). remains al., reconciled et You al., 2011; possibly or al., et et signaling, proliferation, (Louvi VEGF activity and has enhanced ERK PCDC10 increased signaling, survival of Notch loss increase al., reduced and Conversely, et 2010) through to al., (Chen 2012). et reported death Zhu cell 2010; been al., al., to et et linked Lin thereby been 2009; the (Fidalgo proteins, has for expression ERM survival stress, PDCD10 required activates oxidative cell after is and periphery promoting and phosphorylates cell after it 2010) the endocytosis to to where al., 2010). MST4 VEGFR2 al., et leads of induce et relocation (He PDCD10 (He to stimulation protein of appears VEGF VEGFR2 and also loss the complexes pathways PDCD10 and of PDCD10 signaling stability VEGFR2, example, different decreased with For several survival. to colocalizes linked in 1999) pro-apoptopic been involved al., et and has (Wang apoptosis pro-survival and to granulocyte discovered during both cell originally upregulated in was as be PDCD10 PDCD10 reported. for clear been role have not effects a specific play a is to However, thought survival death. is cell PDCD10 suggests, in name role endothelial its of as maintenance for and, essential integrity is death cell of disease. regulation CCM of in observed loss morphology in (Zhang exocytosis tubular a in fusion defective changes vesicle implicates the to potentially of This 2013b). regulator owing al., in a et exocytosis role UNC13D, or with a PDCD10 neutrophil interaction either plays of increases loss also that STK24 shows PDCD10 work recent CCM. and for vascular exocytosis, in essential the to is found lead migration could malformations directed perturbation its As formation, 2013a). vessel do blood al., another one et bind (Zhang to unable not are cell that of increased mutants whereas to overexpression migration, leads Conversely, coexpression PDCD10–MST4 2010). cell or impairs al., PDCD10 which et edge, (Fidalgo leading the complex migration decreased towards Golgi the activity, centrosome both the repositioning kinase and in impaired depleted STK25 are Cells PDCD10 of disassembly. of Golgi loss ultimately and a stability protein to leading 2011), C ein aepo nohla nert.Appropriate integrity. endothelial poor have lesions CCM htha ta. 09.RC niiosas rescue the inhibit and also and KRIT1- 2010) inhibitors al., in et ROCK (Stockton leak 2009). mice 2010; CCM2-deficient vascular al., al., et Stockton lipopolysaccharide-induced by et 2010; rescued al., be monolayer et Whitehead can a (Borikova functions inhibition these of ROCK of KRIT1, three- maintenance Each invasion, lack and barrier. migration, permeability formation in that defective tube Cells 2010), are dimensional PDCD10 activation. al., or RhoA CCM2 might et pathway control PDCD10–STK25–ERM (Zheng the ultimately by down regulated complexes are serine/ actin-associated that knocked membrane-localized GCKIII that is (a suggesting STK25 kinase) partner SMURF1- threonine PDCD10-binding seen promote also the is selectively activity when RhoA Increased might substrates, degradation. SMURF1 RhoA CCM2 other mediated CCM2 of not that of but loss RhoA, suggesting Notably, in 2009). increases al., to et leads (Crose regulatory PTB-domain-mediated (SMURF1) ubiquitin Smad 1 CCM2 ligase factor ubiquitin the a E3 direct the through to with interaction appears RhoA CCM2 of addition, In degradation implicates 2013). al., report et recent (Faurobert a but 2010; elucidated, in al., RhoA–ROCK for et role a Stockton confirming signaling. 2010; CCM 2009), al., al., et et Whitehead (Borikova accumulation oeta hrpui taeyfrCM(iadWieed 2010). Whitehead, one and therefore (Li is CCM for signaling strategy RhoA–ROCK therapeutic (McDonald potential Targeting models mouse 2012). other al., in et lesions vascular of formation oaiaino h TIAM–PAR3–PKC junctional the the of disrupts differentiation deficiency localization cell of KRIT1 endothelial Additionally, induction 2010). venous an for to PDCD10 (Wu essential leads and be signaling, PDCD10 Delta–Notch might or impaired KRIT1 by angiogenesis either S1). for of Table essential Loss material are PDCD10 (supplementary and development CCM2 cardiovascular KRIT1, models, CCMs animal in In permeability and polarity Vascular agt GaigadGnbr,21) ciaino a1(which inhibits Rap1 junctions) of in Activation KRIT1 stabilizes 2010). Ginsberg, and (Glading targets reduces KRIT1 nuclear of increased VE-cadherin, Loss 2007). proteins al., underscored b et junctional The (Glading is p120-catenin the and junctions poster). with cell–cell (see association a in junctions its KRIT1 by cell–cell of disordered importance and weak for its linking important further development. through 2010), vascular al., also migration with et PDCD10 (Fidalgo directed positioning is Golgi and in on effects PDCD10 migration polarization cell directed formation. endothelial impairing lumen 2010), vascular al., et (Lampugnani nrae ncl eso,wihicessdsaiiainof destabilization further increases and which signaling tension, integrin cell altered in ECM, increases abnormal PDCD10 of or in CCM2 results KRIT1, remodeling their this (ECM) of contractility; loss (Faurobert RhoA-dependent above, matrix and noted increases pathology As extracellular CCM 2013). to al., junctions that al., et contribute et also suggest Stockton cell–cell could 2011; data CCM2 remodeling al., mutant Recent et from a (Schneider by 2010). KRIT1 rescued KRIT1 bind is cannot that that of phenotype a destabilization, loss leads also CCM2 to of loss Interestingly, manner. KRIT1-dependent ctnnadV-ahrna elcl ucin,laigto leading junctions, cell–cell at VE-cadherin and -catenin -catenin, o C rtisifuneRo a tl o enfully been not still has RhoA influence proteins CCM How h ek acltr nCMlsosi xlie ytheir by explained is lesions CCM in vasculature leaky The seuee l,21;Yue l,21;Zege al., et Zheng 2013; al., et You 2010; al., et ¨stehube ora fCl cec 21)17 0–0 doi:10.1242/jcs.138388 701–707 127, (2014) Science Cell of Journal b ctnn F aai,as nw sMLLT4) as known also (afadin, AF6 -catenin, b ctnnadurglto fistranscriptional its of upregulation and -catenin b ctnntasrpini a in transcription -catenin f b nernsignaling integrin 1 oaiycomplex polarity

Journal of Cell Science oioa .L,Dbl,C . cay . ec,C . bl,A . Bencharit, N., A. Abell, M., C. Welch, N., Sciaky, F., C. Dibble, L., A. Borikova, C2mttos nM scaatrzdb oso polarity, of loss by characterized is or KRIT1 EndMT a with samples mutations. 2013), patient CCM2 in al., upregulated also et is that (Maddaluno pathway signaling endothelial to BMP6–SMAD due in increased is (EndMT) markers transition endothelial–mesenchymal mesenchymal This of cells. expression increased to patterns lesions. ECM CCM abnormal in the seen explain may This junctions. cell–cell GLANCE A AT SCIENCE CELL ola,G,Rdn,N,Mdauo . Ble L., Maddaluno, N., Rudini, G., Boulday, Ble G., Boulday, and M. J. Zabramski, K., Be G. Steinberg, E., Johnson, L., A. Akers, References at files Individual JPEG jcs.biologists.org. as http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.138388/-/DC2. at available article are downloading this panels for of poster available version is online poster the the in of version high-resolution glance A a at science Cell at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.138388/-/DC1 online available material Supplementary material Supplementary months. Health. 12 of after Institutes release National for the PMC by Research in funded Graduate Deposited are Foundation D.A.C. Science and fellowship. T.J.B. National post-doctoral Fellowship. a Society by Cancer funded American is an O.S.F. by supported is K.M.D. Funding interests. competing no declare authors The interests cited. Competing not is work interactions whose CCM colleagues reported to all apologize of we discussion and detailed preclude limitations Space of functions Acknowledgements known the link formation. further can CCM that neurovasculature to we proteins however, a before CCM clear, necessary in is are It predominantly studies study. results further loss requires phenotype their expressed why widely CCM are of proteins and roles CCM the but vasculature, on the of focused in the has Because proteins work of controversial. much significance phenotype, remains disease the the complex and protein established CCM fully trimeric been not endothelial have in participate cells proteins CCM relevant which The in remain. pathways questions signaling many proteins, and CCM CCM of of functions genetics the the determining in progress significant Despite Conclusions CCM. with TGF patients or lesions, for BMP6 therapeutics whether effective and see CCM be initiation to will interesting inhibitors CCM be in to will contribute It seen progression. might EndMT frequently that suggesting characteristics cell–cell in changes and junctions, migration or proliferation cell in increases ru-uor . ate,R,AbgsRz,C,Cadn .adFaurobert, and P. Chardin, C., Albiges-Rizo, R., Gautier, S., ´raud-Dufour, eerlcvrosmlomto phenotype. malformation cavernous cerebral L. G. Johnson, and S. 5518-5532. C2koku ieetbihteesnilrl fedteilCM in CCM2 endothelial of malformations. role cavernous essential cerebral Mech. human the Model. for establish implications mice angiogenesis: knockout E. CCM2 Tournier-Lasserve, and M. Giovannini, protein-1. associated domain cytoplasmic integrin and Rap1 CCM E. of mechanism two-hit a for evidence pathogenesis. (CCMs): malformations cavernous A. D. Marchuk, hpn . dm,R . eaa .adTune-asre E. Tournier-Lasserve, in and malformations cavernous E. cerebral influences Dejana, mice. loss CCM2 H., of timing R. Developmental Adams, F., Chapon, xiignwdt hwta h oso RT rPC1 leads PDCD10 or KRIT1 of loss the that show data new Exciting 20) rt1itrcin ihmcouue n ebae r euae by regulated are membranes and microtubules with interactions 1 Krit (2007). .Ep Med. Exp. J. cn . ei,N,Caer,F,Gri,L . iaKwkt,M., Niwa-Kawakita, A., L. Garcia, F., Chareyre, N., Petit, A., ´con, 2 u.Ml Genet. Mol. Hum. 168-177. , 20) ilei oai n emiemttosi cerebral in mutations germline and somatic Biallelic (2009). 208 1835-1847. , 21) h iaeihbto ece h nohla cell endothelial the rescues inhibition kinase Rho (2010). 18 919-930. , cn . rol,M,Gurc A., Gaudric, M., Arnould, A., ´con, 20) iseseii conditional Tissue-specific (2009). .Bo.Chem. Biol. J. 285 11760-11764. , ESJ. FEBS (2011). 274 Dis. b , ihr .S,Zag . i . upy .W,Dmlr .adBgo,T J. T. Boggon, and B. Demeler, W., J. Murphy, X., Li, R., Zhang, S., O. Fisher, odeut . ’mrso .M,Ka,M . uln .J,Lre,B G., B. Larsen, J., M. Mullin, J., M. Kean, M., L. D’Ambrosio, M., Goudreault, ibe .F,Hrt .A,Mln,M . ak . epe . heea,H., Cheeseman, B., Temple, K., Park, H., M. Malone, A., J. Horst, F., C. Dibble, iga,A . uo-cagln .adGnbr,M H. M. Ginsberg, and W. Puzon-McLaughlin, R., A. H. Gingras, M. Ginsberg, and J. J. Liu, R., A. Gingras, P., Guazzi, V., Menchise, D., Longo, E., Luca, De M., Avolio, F., Francalanci, Tournier- and C. Albiges-Rizo, E., Faurobert, J., Zalvide, A., Fischer, Zalvide, and M. C. Pombo, C., Iglesias, M., Fraile, A., Guerrero, J. M., Zalvide, Fidalgo, and C. Pombo, T., Force, A., Pires, M., Fraile, M., Fidalgo, C. Rome, E., Faurobert, C. D. Wang, and Y. Zhang, Y., Hu, F., D. Li, X., Wang, J., Ding, eir . aag,P,Braet,F,Mrhli . in,F,Anut M., Arnoult, F., Riant, F., Marchelli, Sure, F., Bergametti, and P., R. Labauge, C., Gerlach, Denier, Y., Zhu, S., Weidensee, U., Hehr, P., K., Soneji, Dammann, W., Li, E., Claudio, E., O’Donnell, Y., Uchida, L. K., G. Cunningham, Johnson, and N. Sciaky, L., T. Hilder, E., L. Crose, F., D. Ceccarelli, Z., Levy, A., Mett, D., J. Knight, V., Ast, J., M. Kean, B., Costa, oe .V,Lmunn,M . y,L,Djn,E n enti,B M. B. Weinstein, and E. Dejana, L., Dye, G., M. Lampugnani, V., Retta, and A. P. Gore, Pinton, S., Marchi, P., Degan, S., Degani, F., Balzac, L., Goitre, ldn,A .adGnbr,M H. M. Ginsberg, and J. A. Glading, C. Albiges-Rizo, and E. Faurobert, hn . aroe,G,Yn,H,Fidadr . ov,A n Gunel, and A. Louvi, R., Friedlander, H., Yano, G., Tanriover, J., Ling, L., C., C. Chen, Gibson, C., A. Smith, E., O. Ruiz, G., S. Drakos, C., A. Chan, and F. R. Spetzler, J., Eales, L., N. Martirosyan, Y., M. Kalani, D., D. Cavalcanti, ldn,A,Hn . tctn .A n iseg .H. M. Ginsberg, and A. R. Stockton, J., Han, A., Glading, oddhlcldmi tisC-terminus. its at reveal (CCM2) domain 2 helical malformations folded cavernous a cerebral of studies Structural (2013). titnitrcigpopaaeadkns ope ikdt h cerebral the to linked protein. al. complex (CCM3) et 3 novel kinase I. a malformation A. identifies and cavernous Nesvizhskii, network F., interaction phosphatase density Sicheri, high striatin-interacting I., phosphatase G. PP2A Chen, A (2009). S., Chaudhry, A., Sanchez, ucinldmi fporme eldah1 hog t neatoswith interactions its S. through Bencharit, 10 and death L. cell programmed G. phosphatidylinositol-3,4,5-trisphosphate. of Johnson, domain R., functional J. Barbaro, patients. malformations cavernous cerebral ucinlacoaeo h eerlcvrosmlomtoscomplex. malformations cavernous cerebral Biol. the of anchorage junctional for framework a isoforms: pathogenesis. KRIT1B CCM and understanding KRIT1A between differences functional Sgro homeostasis. cell endothelial E. Lasserve, stress. oxidative from cells mammalian protect by to ezrin/radixin/moesin Ste20-4 proteins cytoskeletal the of phosphorylation J. cell and assembly Golgi promote to orientation. proteins GCKIII stabilizes CCM3/PDCD10 Ke remodeling. P., fibronectin A. and contractility Bouin, M., al. et Balland, M., Malbouyres, aizk . iat . rnra,L,Tune-asre . Socie E.; Tournier-Lasserve, L., Brunereau, E., Vicaut, Franc J., Maciazek, mutation. germline CCM1/KRIT1 483-486. a with twins monozygotic U. cerebral human of model mouse a brain: malformations. adult cavernous the in U. hemorrhage Siebenlist, causes and Ccm2 S. Y. Mukouyama, H., Wang, cells. 1- endothelial factor in regulatory 13305. degradation ubiquitin smad RhoA promotes origin. mediated protein neural 2 malformation of cavernous cells tumor pediatric in Chem. Biol. death J. protein-dependent Ko CCM2 R., and Eils, G., B. Badillo, 20) obntra neato ewe C aha ee precipitates genes pathway CCM between stroke. hemorrhagic interaction Combinatorial (2008). species. F. S. junctions. cell cell endothelial regulates that 247-254. effector Rap1 a is ohteRp Taeadtehato ls HG)ctpamctail. cytoplasmic (HEG1) Glass of to heart bound (KRIT1) the 1 and Chem Trapped GTPase Interaction Rap1 Krev the of both complex ternary the of structure construction. under puzzle jigsaw complex J. a malformations: cavernous prot adaptor malformation. inositol-(1,3,4,5)- novel cavernous with complexed a 10 death tetrakisphosphate: cell programmed human of structure uain n2dsic eei ahasrsl ncrba cavernous cerebral 3. malformation in cavernous result al. et M. pathways P. M. genetic Revelo, distinct A., mice. in Sacharidou, 2 malformations N., in A. Stratman, Mutations F., S. Passi, disease. to C. M. Preul, euaebt-aei signaling. beta-catenin regulate 21) dpo rti eerlcvrosmlomto CM)mediates (CCM3) 3 malformation cavernous cerebral protein Adaptor (2012). 277 21) w-i ehns ncrba aenu afrain aeof case A malformation? cavernous cerebral in mechanism Two-hit (2013). 20) ppoi ucin fPC1/C3 h eemttdi cerebral in mutated gene the PDCD10/CCM3, of functions Apoptotic (2009). . aio . ote . azc .e al. et F. Balzac, L., Goitre, M., Marino, F., , ` 199 as eNeurochirurgie de ¸aise 21) RT euae h oesai fitaellrratv oxygen reactive intracellular of homeostasis the regulates KRIT1 (2010). 21) C1IA- ope controls complex CCM1-ICAP-1 (2013). . 1084-1096. , 288 39-48. , LSONE PLoS ora fCl cec 21)17 0–0 doi:10.1242/jcs.138388 701–707 127, (2014) Science Cell of Journal 23639-23649. , .Neurosurg. J. .Cl Sci. Cell J. 21) eerlcvrosmlomtos rmgnst proteins to genes from malformations: cavernous Cerebral (2012). 21) eerlcvrosmlomtos rmCMgnsto genes CCM from malformations: cavernous Cerebral (2013). 287 29285-29289. , i.Mdl Mech. Model. Dis. 5 e11786. , .Ci.Invest. Clin. J. 123 ice.Bohs e.Commun. Res. Biophys. Biochem. iosa . Manet-Dupe J., Lisowska, , 116 i,R tal. et R. nig, ¨ u.Ml Genet. Mol. Hum. 1274-1284. , Stroke rnsMl Med. Mol. Trends 122-132. , i.Mdl Mech. Model. Dis. 20) eoyepeoyecreain in correlations Genotype-phenotype (2006). 40 21) a1adisefco KRIT1/CCM1 effector its and Rap1 (2010). x.Cl Res. Cell Exp. 1474-1481. , 121 21) eetisgt nocerebral into insights Recent (2010). 1 .Cl Biol. Cell J. LSONE PLoS 275-281. , 21) T2 rti eitsTrkA mediates protein STK25 (2012). ESLett. FEBS 1871-1881. , o.Cl.Proteomics Cell. Mol. i novdi ua cerebral human in involved ein n.Neurol. Ann. 20 .Bo.Chem. Biol. J. b nerndpnetendothelial integrin-dependent 1 3198-3206. , 21) tutrlbsso the of basis Structural (2012). 19 21) odtoa eeinof deletion Conditional (2011). rmds . ovr,D. Bouvard, M., ´ramidas, .Bo.Chem. Biol. J. 302-308. , 315 3 202 73-83. , 5 587 e11740. , 285-303. , 20) tutrland Structural (2009). 545-561. , ,S,Boulday, G., S., ´, 20) KRIT-1/CCM1 (2007). 60 272-277. , 21) eiigthe Defining (2010). ersr.Rev. Neurosurg. 550-556. , 287 399 20) Cerebral (2009). .Cl Biol. Cell J. 21) Crystal (2010). 11556-11565. , 587-592. , 8 284 21) The (2013). 157-171. , 13301- , (2010). (2011). .Biol. J. .Cell J. FEBS 705 179 36 ´te ´ , ,

Journal of Cell Science i .Y n htha,K J. K. Whitehead, and Y. D. Li, ae,L,Csa . cepkv . aak,M,Oetur . asod .M., L. Hansford, A., Oberthuer, M., Zapatka, M., Tcherpakov, B., Costa, L., Harel, P. R. Lifton, G., and Luleci, J., L. Voorhees, M., Trabalzini, N. Amankulor, C., O., Martino, Guzeloglu-Kayisli, V., Cutano, E., Ferro, L., Goitre, P., Guazzi, GLANCE A AT SCIENCE CELL 706 M. Vikkula, and M. L. Boon, N., Limaye, J. T. Boggon, and A. D. Calderwood, W., Liu, M., K. Draheim, R., Zhang, X., Li, Chapon, G., Boulday, L., Sweeney, Maddaluno, N., Z., Rudini, F., Zou, Orsenigo, G., J., M. Lampugnani, J. Tung, Y., Blum, J., J. Liu, X., Zheng, B., Kleaveland, L. G. Johnson, and H. M. Malone, L., T. Hilder, coad .A,Si . hna,R,Soko,R . i,F,Ginsberg, F., Liu, A., R. Stockton, R., Shenkar, L., C., A. Shi, Akers, A., D. A., McDonald, R. Stockton, C., Shi, R., Shenkar, A., D. McDonald, M., Corada, C., Giampietro, L., Bravi, and R., N. Cuttano, N., J. Rudini, Chen, L., A., Maddaluno, M. Mohideen, C., F. Serluca, C. P., M. L. Fishman, Chuang, and D., N. J. J. Mably, Chen, G., C. Burns, A., M. Mohideen, D., J. Gu Mably, and W. Min, H., Zhang, M., A. Two, L., Chen, A., Louvi, Bobkov, J., Han, J., A. Ablooglu, R., A. Gingras, A., R. Stockton, J., J. Liu, Stoffer, S., J. Zawistowski, E., Huang, M., A. Siegel, J., M. Berg, L., C. Liquori, X. Wang, and T. Zhu, S., Meng, C., Lin, i . i . hn,R,FlaSone,E,Mn .adBgo,T J. T. Boggon, and W. Min, E., Folta-Stogniew, J. R., T. Zhang, Boggon, W., and Ji, W. X., Min, Li, W., Ji, Y., He, H., Zhang, R., Zhang, X., Li, B., Larsen, S., Tate, M., Sanches, M., Goudreault, F., D. Ceccarelli, J., M. Kean, S. Schulte-Merker, and H. Wolburg, J., Bussmann, M., B. Hogan, A., T. Haystead, J., Colicelli, S., Bencharit, H., M. Malone, L., T. W. Hilder, Min, and H. Chen, J., T. Boggon, M., Gunel, L., Yu, H., Zhang, Y., He, i,W,Daem .M,Zag . adrod .A n ogn .J. T. Boggon, and A. D. Calderwood, R., Zhang, M., K. Draheim, W., Liu, 21) tutrlbssfrsalGpoenefco neato fRas-related (KRIT1). of 1 trapped interaction interaction effector Krev protein protein Chem. adaptor G and (Rap1) small 1 for protein basis Structural (2012). malformations. cavernous cerebral polarity. endothelial E. Dejana, malformation and F. cavernous glass-cerebral of heart the pathway. by protein integrity and development S.M.,Chen,M.,Guo,L.,Lu,M.M.etal. scaffolding. kinase protein mitogen-activated of kinase. tyrosine receptor TrkA al. the et by S. F. signaling Lee, Y., Z. Chen, Z., adult Levy, M., Vojvodic, the of cells pyramidal and cortex. astrocytes, cerebral human endothelium, vascular to M. localizes Gunel, and KRIT1. of interactor molecular F. S. Retta, nagn noiganvlpoencnann phosphotyrosine-binding a containing protein novel a encoding al. gene et P. T. a Leedom, L., in Hughes, F., Balogun, D., Verlaan, T., 41675-41685. anomalies. vascular of R1 pathophysiology the in mutations namrn oe fcrba aenu afraindisease. malformation cavernous cerebral of 574. A. model I. murine Awad, a and in disease. A. D. human Marchuk, H., the M. recapitulates hypothesis mutation Genet. Awad, two-hit Mol. H., Hum. the M. Ginsberg, on J., based al. Brainer, et R., A. Kucherlapati, I. H., al. M. Kucherlapati, et malformations. G. cavernous cerebral Boulday, of progression E., and Nature Papa, onset the F., to Orsenigo, contributes L., Ferrarini, zebrafish. the in myocardium C. zebrafish. M. in Fishman, heart the of growth concentric the Biol. regulates Curr. and glass of CCM heart to (2003). leads neuroglia in (Ccm3) 3 pathology. malformation vascular cavernous cerebral of junctions. cell – cell H. endothelial M. of Ginsberg, and A. A. malformations. cavernous cerebral 2 73 type cause domain oeua eonto fluieapraerpa L)mtf ytefocal 3 the malformation cavernous by cerebral motifs of (LD) domain repeat (CCM3). homology leucine-aspartate targeting of adhesion recognition Molecular for critical protein malformation cavernous integrity. cerebral vascular a CCM3, of structure Crystal in implicated al. complex et signaling L. a Pelletier, proteins: C., polarization. STRIPAK I. Golgi core Scott, of B., analysis W. function Derry, C., L. Gibson, vascular and morphogenesis zebrafish. cellular in endothelial tubulogenesis regulates autonomously cell 312. complex. signaling C. C. malformation is Wu, cavernous and 3 L. G. malformation Johnson, cavernous cerebral development. by vascular signaling for critical VEGFR2 of Stabilization 21) ehns o RT ees fIA1mdae upeso of suppression ICAP1-mediated of release KRIT1 activation. for integrin Mechanism (2013). survival. neuronal regulate to gamma-protocadherins of 1459-1464. , R65-R74. , 287 498 .Bo.Chem. Biol. J. 13 22317-22327. , 21) oe os oe fcrba aenu malformations cavernous cerebral of model mouse novel A (2011). 492-496. , 21) dniiaino h ec aiypoenN1La novel a as Nd1-L protein family Kelch the of Identification (2012). 2138-2147. , a.Med. Nat. 20) at n aetn atr ocnrcgot fcardiac of growth concentric pattern valentine and santa (2006). 21) C1rgltsvsua-ue raiainb inducing by organization vascular-lumen regulates CCM1 (2010). 20) RT/eerlcvrosmlomto protein 1 malformation cavernous KRIT1/cerebral (2004). .Bo.Chem. Biol. J. 20 .Cl Sci. Cell J. .Bo.Chem. Biol. J. o.Cell Mol. rc al cd c.USA Sci. Acad. Natl. Proc. 211-222. , Neurosurgery 286 15 u.Ml Genet. Mol. Hum. 21) ehns fRp-nue stabilization Rap1-induced of mechanism A (2011). 26138-26147. , 49 169-176. , 123 Development 21) vlaigsrtge o h ramn of treatment the for strategies Evaluating (2010). LSONE PLoS 719-729. , 20a.Poemcietfcto ftecerebral the of identification Proteomic (2007a). 1073-1080. , 285 c.Signal. Sci. 286 o.Bo.Cell Biol. Mol. Stroke 24099-24107. , 25065-25075. , 21) DD0CM csdownstream acts PDCD10/CCM3 (2010). 54 21) aui erae einburden lesion decreases Fasudil (2012). 20) rmgrln oad somatic towards germline From (2009). 4-4,dsuso 949. discussion 943-949, , 1Suppl. 41 7 20) euaino cardiovascular of Regulation (2009). 133 e44705. , .Poem Res. Proteome J. 3 17 20b.Hprsoi induction Hyperosmotic (2007b). Neuron ra26. , 3139-3146. , 108 2424-2432. , ehd Enzymol. Methods 22 20) C2mdae death mediates CCM2 (2009). 3737-3742. , 2509-2519. , S92-S94. , 63 585-591. , u.Ml Genet. Mol. Hum. e,M. nel, ¨ m .Hm Genet. Hum. J. Am. .Bo.Chem. Biol. J. 21) Structure- (2011). 20) Mutations (2003). 6 21) EndMT (2013). Stroke 4343-4355. , 20) ccm1 (2008). 21) Loss (2011). 428 43 (2010). (2010). (2011). .Biol. J. 297- , 571- , 285 18 , ag . i,H,Zag .adM,D. Ma, and Y. Zhang, H., Liu, Y., Wang, Schulte-Merker, E., Schleider, and J., Reinders, D. M., T. B. Mueller, Hogan, S., J., Stahl, Nickel, K., Voss, S., Ullrich, E., Schleider, S., Stahl, K., Voss, K. Lobel-Rice, D., B. Cuevas, W., Sun, L., N. Johnson, N., A. N. Abell, T., Demir, M. Uhlik, and M. Gunel, T., Kilic, A., Seker, B., Sozen, G., Tanriover, A. Clerk, and J. L. McGuffin, H., P. Sugden, tctn .A,Sekr . wd .A n iseg .H. M. Ginsberg, and A. I. Awad, R., Shenkar, A., R. Stockton, Su E., Schleider, B., Brackertz, K., Voss, S., Gaetzner, S., Stahl, ee,A,Pioa .L,Gcu . zuk .K,Lui .adGunel, and A. A. Louvi, E. Golemis, K., and R. A. J. Testa, Ozturk, G., Sonoda, B., J., Estojak, Guclu, I., Serebriiskii, L., K. Pricola, A., Seker, D. J. Mably, and Y. S L. c h Ye, n M., e i V. d e Sogah, r N., ,H . J. ,E rRosen, r e d e E. ,M Tournier-Lasserve, . ,U and l P. r i Saugier-Veber, c M., h ,N Cecillon, .H F., . ,VRiant, i r g i n t i n o ,D . ,F r e i ,K .a n dB e r t a l a n f f y ,H . lme,N . qie .L,Siiaa,S,Hag . aitwk,J S., J. Zawistowski, E., Huang, S., Srinivasan, L., T. Squire, W., N. Plummer, aitwk,J . tlem . hi,M . bl,A . nrl,B B., B. Ancrile, N., A. Abell, T., M. Uhlik, L., Stalheim, S., J. Zawistowski, Wu R., N. London, W., Koh, S., Navankasattusas, C., Y. A. D. Chan, Li, J., and K. A. Whitehead, D. Marchuk, A., J. Adams, W., N. Plummer, J., K. Whitehead, aesehr . th,S,Sr,U n ebr U. Felbor, and U. Sure, S., Stahl, A., Pagenstecher, Millon-Fre o,C,Snacol,I . amn,P,Flo,U,Sr,U n Zhu, and U. Sure, U., Felbor, P., Dammann, E., I. Sandalcioglu, C., C. You, I. Scott, and C. N. Chi, S., B. Gillers, B., Yoruk, J. Ding, and C. D. Wang, Y., Zhang, X., Wang, X., Xu, lme,N . aloe .J,Siiaa,S,Zwsosi .S,Lus .N. D. Louis, S., J. Zawistowski, S., Srinivasan, J., C. Gallione, W., N. Plummer, Ble N., Petit, cdi-rm eeinpv h a o oanmpigo h cerebral the of mapping domain for way the protein. pave 3 malformation deletion cavernous in-frame acid U. Felbor, and S. malformations. cavernous cerebral for U. Felbor, L. shock. G. hyperosmotic during Johnson, activation and Biol. MAPK L. p38 M. for scaffolding Dell’Acqua, MKK3 A., E. Horne, E., Neurosurg. malformations. cavernous Neurol. cerebral Clin. in features vascular of analysis heterologous Ultrastructural their and kinases III) kinase interactions. centre protein-protein (germinal GCKIII the STicKs: aenu afrain rtisihbtRokns osaiievascular stabilize to kinase Rho inhibit proteins integrity. malformations cavernous protein CCM1/CCM2/CCM3 a of formation al. prevents malformations: et complex. cavernous CCM2 U. cerebral in with deletion Finckh, patients in-frame in C., mutations Korenke, CCM3 and C., CCM2, Netzer, E., Kunze, noe yagn apn o7q21-22. to mapping protein gene repeat-containing ankyrin a novel by a encoded Krit1, with Krev-1/rap1a of Association M. of cells endothelial in transport malformations. glucose cavernous cerebral and human junctions tight of Impairment (2011). Heg-CCM the of component novel a pathway. as development cardiovascular for required variants deletions. large unclassified of novel importance context: and 14 diagnosis splicing abnormal a to in leading screening molecular CCM h c2gn nanwmuemdlo eerlcvrosmalformations. cavernous cerebral of model mouse new a Genome in Mamm. A. gene D. Ccm2 Marchuk, and the P. L. Hale, H., Matsunami, c1(RT)t eeomn fcrba aclrmalformations. vascular cerebral of development to Pathol. (KRIT1) A. Ccm1 D. Marchuk, and ono,G .adMrhk .A. D. Marchuk, and L. G. Johnson, al. et W. Zhu, integrity A., GTPases. vascular C. promotes Rho Jones, pathway via G., signaling S. malformation Drakos, cavernous H., cerebral A. Mayo, J., Ling, etiology the malformations. for cavernous implications morphogenesis: human arterial of for required is Ccm1 (2004). 329. gene. humanTFAR15 gene, apoptosis-related an est scnrle yIA--eedn ea-nernaffinity. beta1-integrin ICAP-1-dependent by 180 controlled is density C. Albiges-Rizo, and nohla nignssadi neie eerlcvrosmalformations. cavernous cerebral Med. inherited Mol. Cell. in J. and angiogenesis vascular endothelial CCM of model Y. zebrafish a in Ccm2 and Ccm1 disease. from distinct manner III. 3 kinase malformation center cavernous germinal cerebral and between assembly heterodimeric DELTA-NOTCH unique the activating by angiogenesis sprouting signaling. inhibits A. CCM1 Fischer, and protein G. H. Augustin, U., xrsino h he eerlcvrosmlomto CM ee during genes (CCM) development. malformation brain cavernous postnatal cerebral and embryonic three the of expression cells. endothelial affected inactivation in CCM3 complete 911-918. or malformations: CCM2 CCM1, cavernous of cerebral causes mechanism thb,J,Bro,A,Lelr .S,Bru S., S. Liebler, A., Bartol, J., stehube, ¨ 133-141. , 20) C2epeso aall hto CCM1. of that parallels expression CCM2 (2006). 21) oso C3ipisDL-oc inlig mlcto in implication signalling: DLL4-Notch impairs CCM3 of Loss (2013). 427-441. , 5 1104-1110. , mlo,A,Buad . rcie . Manet-Dupe A., Grichine, D., Bouvard, A., ´millon, 165 .Ep Med. Exp. J. e.Biol. Dev. e.Biol. Dev. ora fCl cec 21)17 0–0 doi:10.1242/jcs.138388 701–707 127, (2014) Science Cell of Journal u.Mutat. Hum. cn . eir .adTune-asre E. Tournier-Lasserve, and C. Denier, A., ´con, rc al cd c.USA Sci. Acad. Natl. Proc. 20) C3itrcswt C2idctn omnpathogenesis common indicating CCM2 with interacts CCM3 (2007). 1509-1518. , 17 20) ucinlaaye fhmnadzbaih18-amino zebrafish and human of analyses Functional (2009). 17 a.Med. Nat. 362 376 119-128. , 407-418. , 20) oso 5 estzsmc ihamtto in mutation a with mice sensitizes p53 of Loss (2004). 207 29 121-131. , 20) elaatv epnet xrclua matrix extracellular to response adaptive Cell (2008). 74-85. , 115 709-717. , 881-896. , ice.J. Biochem. 438-444. , 15 Structure 177-184. , u.Mutat. Hum. Development 21) eerlcvrosmalformation cavernous Cerebral (2010). 107 Neurogenetics 19) DAcoigadepeso of expression and cloning cDNA (1999). .Nuoahl x.Neurol. Neuropathol. Exp. J. 454 21 Oncogene 12640-12645. , 20) C1adCM protein CCM2 and CCM1 (2005). sh . h,Y,Flo,U,Sure, U., Felbor, Y., Zhu, R., tsch, ¨ 1059-1066. , 13-30. , 21) OK iT,MS and MASK MiSTs, SOcK, (2013). eeEp.Patterns Expr. Gene 20) ernlepeso of expression Neuronal (2006). 30 c.CiaCLf Sci. Life C China Sci. 1003-1011. , 131 21) c3fntosi a in functions Ccm3 (2012). 21) tutrlbssfor basis Structural (2013). 15 Stroke 8 1437-1448. , 249-256. , 1043-1049. , u.Ml Genet. Mol. Hum. 20) oe CCM1, Novel (2008). 20) Rac-MEKK3- (2003). 21) c2lk is ccm2-like (2013). 20) atrsof Patterns (2006). ,S,Bok .R. M. Block, S., ´, 20) two-hit A (2009). 37 21) Cerebral (2010). 518-523. , Neurogenetics .Cl Biol. Cell J. 70 6 20) The (2009). 495-503. , ¨ru 417-429. , a.Cell Nat. ¨cu 42 (1997). (2013). m J. Am. (2013). O., , ¨ 323- , 18 ,

Journal of Cell Science hn,X,X,C,D oez,A,Kevln,B,Zu . elr . hn M., Chen, C., Seiler, Z., Zou, B., Kleaveland, A., Lorenzo, Di W., C., Pan, Xu, K., X., Zheng, Gao, J., Zhang, Y., Xu, X., Niu, H., Zhang, W., Tang, Y., Zhang, ELSINEA GLANCE A AT SCIENCE CELL hn,M,Dn,L,Si . io . hn,Z,Zag . i,G,Ce,C,Feng, C., Chen, G., Liu, W., Zhang, Z., Zhang, S., Jiao, Z., Shi, L., Dong, M., Zhang, E. R. Clatterbuck, and C. H. Dietz, D., Rigamonti, J., Zhang, iae ly nesnilrl uigzbaihcrivsua development cardiovascular zebrafish during malformations. cavernous role cerebral essential in and al. an et Exocytosis plays J. He, kinases Vesicle J., Xiao, L., UNC13D-Driven Cheng, Coordinate to STK24 Neutrophils. al. and et D. CCM3 Toomre, J., T. Boggon, CIIkinases. GCKIII cerebral of M.,Hao,Q.etal. pathogenesis the for implications malformations. malcavernin: cavernous and krit1 between malformations cavernous cerebral for implications pathogenesis. signaling: cell in interactions e.Cell Dev. u.Ml Genet. Mol. Hum. Structure 21a.Srcua ehns of mechanism Structural (2013a). 27 21 215-226. , Neurosurgery 680-688. , 21) C3sgaigtruhseie20-like sterile through signaling CCM3 (2010). 14 21b.ANtoko neatosEnables Interactions of Network A (2013b). 2521-2531. , .Ci.Invest. Clin. J. 60 5-5,dsuso 359. discussion 353-359, , C3htrdmrzto with heterodimerization CCM3 120 2795-2804. , 20) Interaction (2007). h,Y,W,Q,X,J . ilr . adligu .E,Zag .M n Sure, and M. J. Zhu,Y.,Wu,Q.,Fass,M.,Xu,J.F.,You,C.,Mu Zhang, E., I. Sandalcioglu, D., Miller, F., J. Xu, Q., Wu, Y., Zhu, hu . zm,Y,Br,M .adFrai,J D. J. Ferraris, and B. M. Burg, Y., Izumi, X., Zhou, Yuan, B., Kleaveland, Z., Zou, N., A. Stratman, O., A. Smith, C., Xu, X., Zheng, hntp n eoyeo h nohladrvdfo prdccerebral sporadic from derived 732. endothelia malformations. the of cavernous genotype and U. phenotype Sure, and M. J. Zhang, malformations. cavernous U. 12155-12160. cfodfrMK3cnrbtsvapopoiaeCgma oatvto of activation to C-gamma1 NFAT5. factor phospholipase transcription via osmoprotective contributes the MEKK3 for scaffold growth. and stability vascular controls al. Cell et pathway X. malformation Liu, A., cavernous Sen, C., Didiku, L., 21) ifrnilagoeei ucino C2adCM ncerebral in CCM3 and CCM2 of function angiogenesis Differential (2010). 23 342-355. , ora fCl cec 21)17 0–0 doi:10.1242/jcs.138388 701–707 127, (2014) Science Cell of Journal ersr.Focus Neurosurg. 21) nvtocaatrzto fteangiogenic the of characterization vitro In (2011). Neurosurgery 21) yai euaino h cerebral the of regulation Dynamic (2012). 29 69 rc al cd c.USA Sci. Acad. Natl. Proc. E1. , lr . adligu .E., I. Sandalcioglu, O., ller, ¨ 2-3,dsuso 731- discussion 722-731, , 21) Rac1/osmosensing (2011). 707 Dev. 108 ,

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