Cellular and Molecular Life Sciences

, Volume 71, Issue 10, pp 1881–1892 | Cite as

Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology

  • Oriana S. Fisher
  • Titus J. BoggonEmail author


Cerebral cavernous malformations (CCM) are neurovascular dysplasias that result in mulberry-shaped lesions predominantly located in brain and spinal tissues. Mutations in three genes are associated with CCM. These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell death 10 (CCM3/PDCD10). There have been many significant recent advances in our understanding of the structure and function of these proteins, as well as in their roles in cellular signaling. Here, we provide an update on the current knowledge of the structure of the CCM proteins and their functions within cellular signaling, particularly in cellular adhesion complexes and signaling cascades. We go on to discuss subcellular localization of the CCM proteins, the formation and regulation of the CCM complex signaling platform, and current progress towards targeted therapy for CCM disease. Recent structural studies have begun to shed new light on CCM protein function, and we focus here on how these studies have helped inform the current understanding of these roles and how they may aid future studies into both CCM-related biology and disease mechanisms.


Cerebral cavernous malformations CCM complex signaling platform Neurovasculature Integrin signaling Kinases 



O.S.F. is funded by a National Science Foundation Graduate Research Fellowship. T.J.B. is funded by National Institutes of Health grants R01GM102262, R01NS085078, and R01GM100411.


  1. 1.
    Labauge P, Denier C, Bergametti F, Tournier-Lasserve E (2007) Genetics of cavernous angiomas. Lancet Neurol 6(3):237–244PubMedGoogle Scholar
  2. 2.
    Cavalcanti DD, Kalani MY, Martirosyan NL, Eales J, Spetzler RF, Preul MC (2012) Cerebral cavernous malformations: from genes to proteins to disease. J Neurosurg 116(1):122–132PubMedGoogle Scholar
  3. 3.
    Revencu N, Vikkula M (2006) Cerebral cavernous malformation: new molecular and clinical insights. J Med Genet 43(9):716–721PubMedCentralPubMedGoogle Scholar
  4. 4.
    Yadla S, Jabbour PM, Shenkar R, Shi C, Campbell PG, Awad IA (2010) Cerebral cavernous malformations as a disease of vascular permeability: from bench to bedside with caution. Neurosurg Focus 29(3):E4PubMedGoogle Scholar
  5. 5.
    Otten P, Pizzolato GP, Rilliet B, Berney J (1989) [131 cases of cavernous angioma (cavernomas) of the CNS, discovered by retrospective analysis of 24,535 autopsies]. Neurochirurgie 35(2):82–83, 128–131Google Scholar
  6. 6.
    Riant F, Bergametti F, Ayrignac X, Boulday G, Tournier-Lasserve E (2010) Recent insights into cerebral cavernous malformations: the molecular genetics of CCM. FEBS J 277(5):1070–1075PubMedGoogle Scholar
  7. 7.
    Krisht KM, Whitehead KJ, Niazi T, Couldwell WT (2010) The pathogenetic features of cerebral cavernous malformations: a comprehensive review with therapeutic implications. Neurosurg Focus 29(3):E2PubMedGoogle Scholar
  8. 8.
    Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA (2009) Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet 18(5):919–930PubMedCentralPubMedGoogle Scholar
  9. 9.
    Pagenstecher A, Stahl S, Sure U, Felbor U (2009) A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Hum Mol Genet 18(5):911–918PubMedCentralPubMedGoogle Scholar
  10. 10.
    Gault J, Shenkar R, Recksiek P, Awad IA (2005) Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke 36(4):872–874PubMedGoogle Scholar
  11. 11.
    Boulday G, Rudini N, Maddaluno L, Blecon A, Arnould M, Gaudric A, Chapon F, Adams RH, Dejana E, Tournier-Lasserve E (2011) Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice. J Exp Med 208(9):1835–1847PubMedCentralPubMedGoogle Scholar
  12. 12.
    Dammann P, Hehr U, Weidensee S, Zhu Y, Gerlach R, Sure U (2013) Two-hit mechanism in cerebral cavernous malformation? A case of monozygotic twins with a CCM1/KRIT1 germline mutation. Neurosurg Rev 36(3):483–486PubMedGoogle Scholar
  13. 13.
    Plummer NW, Zawistowski JS, Marchuk DA (2005) Genetics of cerebral cavernous malformations. Curr Neurol Neurosci Rep 5(5):391–396PubMedGoogle Scholar
  14. 14.
    Denier C, Labauge P, Bergametti F, Marchelli F, Riant F, Arnoult M, Maciazek J, Vicaut E, Brunereau L, Tournier-Lasserve E (2006) Genotype-phenotype correlations in cerebral cavernous malformations patients. Ann Neurol 60(5):550–556PubMedGoogle Scholar
  15. 15.
    Dubovsky J, Zabramski JM, Kurth J, Spetzler RF, Rich SS, Orr HT, Weber JL (1995) A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet 4(3):453–458PubMedGoogle Scholar
  16. 16.
    Gunel M, Awad IA, Anson J, Lifton RP (1995) Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21. Proc Natl Acad Sci USA 92(14):6620–6624PubMedCentralPubMedGoogle Scholar
  17. 17.
    Gunel M, Awad IA, Finberg K, Anson JA, Steinberg GK, Batjer HH, Kopitnik TA, Morrison L, Giannotta SL, Nelson-Williams C, Lifton RP (1996) A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. N Engl J Med 334(15):946–951PubMedGoogle Scholar
  18. 18.
    Sahoo T, Johnson EW, Thomas JW, Kuehl PM, Jones TL, Dokken CG, Touchman JW, Gallione CJ, Lee-Lin SQ, Kosofsky B, Kurth JH, Louis DN, Mettler G, Morrison L, Gil-Nagel A, Rich SS, Zabramski JM, Boguski MS, Green ED, Marchuk DA (1999) Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 8(12):2325–2333PubMedGoogle Scholar
  19. 19.
    Laberge-le Couteulx S, Jung HH, Labauge P, Houtteville JP, Lescoat C, Cecillon M, Marechal E, Joutel A, Bach JF, Tournier-Lasserve E (1999) Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 23(2):189–193PubMedGoogle Scholar
  20. 20.
    Liquori CL, Berg MJ, Siegel AM, Huang E, Zawistowski JS, Stoffer T, Verlaan D, Balogun F, Hughes L, Leedom TP, Plummer NW, Cannella M, Maglione V, Squitieri F, Johnson EW, Rouleau GA, Ptacek L, Marchuk DA (2003) Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 73(6):1459–1464PubMedCentralPubMedGoogle Scholar
  21. 21.
    Guclu B, Ozturk AK, Pricola KL, Bilguvar K, Shin D, O’Roak BJ, Gunel M (2005) Mutations in apoptosis-related gene, PDCD10, cause cerebral cavernous malformation 3. Neurosurgery 57(5):1008–1013PubMedGoogle Scholar
  22. 22.
    Bergametti F, Denier C, Labauge P, Arnoult M, Boetto S, Clanet M, Coubes P, Echenne B, Ibrahim R, Irthum B, Jacquet G, Lonjon M, Moreau JJ, Neau JP, Parker F, Tremoulet M, Tournier-Lasserve E (2005) Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 76(1):42–51PubMedCentralPubMedGoogle Scholar
  23. 23.
    Boulday G, Blecon A, Petit N, Chareyre F, Garcia LA, Niwa-Kawakita M, Giovannini M, Tournier-Lasserve E (2009) Tissue-specific conditional CCM2 knockout mice establish the essential role of endothelial CCM2 in angiogenesis: implications for human cerebral cavernous malformations. Dis Model Mech 2(3–4):168–177PubMedCentralPubMedGoogle Scholar
  24. 24.
    Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London NR, Ling J, Mayo AH, Drakos SG, Jones CA, Zhu W, Marchuk DA, Davis GE, Li DY (2009) The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med 15(2):177–184PubMedCentralPubMedGoogle Scholar
  25. 25.
    Kleaveland B, Zheng X, Liu JJ, Blum Y, Tung JJ, Zou Z, Sweeney SM, Chen M, Guo L, Lu MM, Zhou D, Kitajewski J, Affolter M, Ginsberg MH, Kahn ML (2009) Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway. Nat Med 15(2):169–176PubMedCentralPubMedGoogle Scholar
  26. 26.
    He, Y, Zhang, H, Yu, L, Gunel, M, Boggon, TJ, Chen, H and Min, W (2010) Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Sci Signal 3(116):ra26Google Scholar
  27. 27.
    Voss K, Stahl S, Schleider E, Ullrich S, Nickel J, Mueller TD, Felbor U (2007) CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics 8(4):249–256PubMedGoogle Scholar
  28. 28.
    Mably JD, Chuang LP, Serluca FC, Mohideen MA, Chen JN, Fishman MC (2006) Santa and valentine pattern concentric growth of cardiac myocardium in the zebrafish. Development 133(16):3139–3146PubMedGoogle Scholar
  29. 29.
    Chan AC, Drakos SG, Ruiz OE, Smith AC, Gibson CC, Ling J, Passi SF, Stratman AN, Sacharidou A, Revelo MP, Grossmann AH, Diakos NA, Davis GE, Metzstein MM, Whitehead KJ, Li DY (2011) Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice. J Clin Invest 121(5):1871–1881PubMedCentralPubMedGoogle Scholar
  30. 30.
    Louvi A, Chen L, Two AM, Zhang H, Min W, Gunel M (2011) Loss of cerebral cavernous malformation 3 (Ccm3) in neuroglia leads to CCM and vascular pathology. Proc Natl Acad Sci USA 108(9):3737–3742PubMedCentralPubMedGoogle Scholar
  31. 31.
    Cunningham K, Uchida Y, O’Donnell E, Claudio E, Li W, Soneji K, Wang H, Mukouyama YS, Siebenlist U (2011) Conditional deletion of Ccm2 causes hemorrhage in the adult brain: a mouse model of human cerebral cavernous malformations. Hum Mol Genet 20(16):3198–3206PubMedCentralPubMedGoogle Scholar
  32. 32.
    McDonald DA, Shenkar R, Shi C, Stockton RA, Akers AL, Kucherlapati MH, Kucherlapati R, Brainer J, Ginsberg MH, Awad IA, Marchuk DA (2011) A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease. Hum Mol Genet 20(2):211–222PubMedCentralPubMedGoogle Scholar
  33. 33.
    Liu H, Rigamonti D, Badr A, Zhang J (2011) Ccm1 regulates microvascular morphogenesis during angiogenesis. J Vasc Res 48(2):130–140PubMedCentralPubMedGoogle Scholar
  34. 34.
    Serebriiskii I, Estojak J, Sonoda G, Testa JR, Golemis EA (1997) Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22. Oncogene 15(9):1043–1049PubMedGoogle Scholar
  35. 35.
    Zhang J, Clatterbuck RE, Rigamonti D, Chang DD, Dietz HC (2001) Interaction between krit1 and icap1alpha infers perturbation of integrin beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation. Hum Mol Genet 10(25):2953–2960PubMedGoogle Scholar
  36. 36.
    Francalanci F, Avolio M, De Luca E, Longo D, Menchise V, Guazzi P, Sgro F, Marino M, Goitre L, Balzac F, Trabalzini L, Retta SF (2009) Structural and functional differences between KRIT1A and KRIT1B isoforms: a framework for understanding CCM pathogenesis. Exp Cell Res 315(2):285–303PubMedGoogle Scholar
  37. 37.
    Beraud-Dufour S, Gautier R, Albiges-Rizo C, Chardin P, Faurobert E (2007) Krit 1 interactions with microtubules and membranes are regulated by Rap1 and integrin cytoplasmic domain associated protein-1. FEBS J 274(21):5518–5532PubMedCentralPubMedGoogle Scholar
  38. 38.
    Sahoo T, Goenaga-Diaz E, Serebriiskii IG, Thomas JW, Kotova E, Cuellar JG, Peloquin JM, Golemis E, Beitinjaneh F, Green ED, Johnson EW, Marchuk DA (2001) Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene. Genomics 71(1):123–126PubMedGoogle Scholar
  39. 39.
    Zhang J, Clatterbuck RE, Rigamonti D, Dietz HC (2000) Cloning of the murine Krit1 cDNA reveals novel mammalian 5’ coding exons. Genomics 70(3):392–395PubMedGoogle Scholar
  40. 40.
    Eerola I, McIntyre B, Vikkula M (2001) Identification of eight novel 5′-exons in cerebral capillary malformation gene-1 (CCM1) encoding KRIT1. Biochim Biophys Acta 1517(3):464–467PubMedGoogle Scholar
  41. 41.
    Zhang J, Rigamonti D, Dietz HC, Clatterbuck RE (2007) Interaction between krit1 and malcavernin: implications for the pathogenesis of cerebral cavernous malformations. Neurosurgery 60(2):353–359PubMedGoogle Scholar
  42. 42.
    Liu W, Draheim KM, Zhang R, Calderwood DA, Boggon TJ (2013) Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin activation. Mol Cell 49(4):719–729PubMedCentralPubMedGoogle Scholar
  43. 43.
    Bessman MJ, Frick DN, O’Handley SF (1996) The MutT proteins or “Nudix” hydrolases, a family of versatile, widely distributed, “housecleaning” enzymes. J Biol Chem 271(41):25059–25062PubMedGoogle Scholar
  44. 44.
    Boudeau J, Miranda-Saavedra D, Barton GJ, Alessi DR (2006) Emerging roles of pseudokinases. Trends Cell Biol 16(9):443–452PubMedGoogle Scholar
  45. 45.
    Li X, Zhang R, Draheim KM, Liu W, Calderwood DA, Boggon TJ (2012) Structural basis for small G protein effector interaction of Ras-related protein 1 (Rap1) and adaptor protein Krev interaction trapped 1 (KRIT1). J Biol Chem 287(26):22317–22327PubMedCentralPubMedGoogle Scholar
  46. 46.
    Gingras AR, Puzon-McLaughlin W, Ginsberg MH (2013) The structure of the ternary complex of krev interaction trapped 1 (KRIT1) bound to both the Rap1 GTPase and the heart of glass (HEG1) cytoplasmic tail. J Biol Chem 288(33):23639–23649PubMedGoogle Scholar
  47. 47.
    Gingras AR, Liu JJ, Ginsberg MH (2012) Structural basis of the junctional anchorage of the cerebral cavernous malformations complex. J Cell Biol 199(1):39–48PubMedCentralPubMedGoogle Scholar
  48. 48.
    Denier C, Goutagny S, Labauge P, Krivosic V, Arnoult M, Cousin A, Benabid AL, Comoy J, Frerebeau P, Gilbert B, Houtteville JP, Jan M, Lapierre F, Loiseau H, Menei P, Mercier P, Moreau JJ, Nivelon-Chevallier A, Parker F, Redondo AM, Scarabin JM, Tremoulet M, Zerah M, Maciazek J, Tournier-Lasserve E (2004) Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 74(2):326–337PubMedCentralPubMedGoogle Scholar
  49. 49.
    Zawistowski JS, Stalheim L, Uhlik MT, Abell AN, Ancrile BB, Johnson GL, Marchuk DA (2005) CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet 14(17):2521–2531PubMedGoogle Scholar
  50. 50.
    Harel L, Costa B, Tcherpakov M, Zapatka M, Oberthuer A, Hansford LM, Vojvodic M, Levy Z, Chen ZY, Lee FS, Avigad S, Yaniv I, Shi L, Eils R, Fischer M, Brors B, Kaplan DR, Fainzilber M (2009) CCM2 mediates death signaling by the TrkA receptor tyrosine kinase. Neuron 63(5):585–591PubMedGoogle Scholar
  51. 51.
    Crose LE, Hilder TL, Sciaky N, Johnson GL (2009) Cerebral cavernous malformation 2 protein promotes smad ubiquitin regulatory factor 1-mediated RhoA degradation in endothelial cells. J Biol Chem 284(20):13301–13305PubMedCentralPubMedGoogle Scholar
  52. 52.
    Fisher OS, Zhang R, Li X, Murphy JW, Demeler B, Boggon TJ (2013) Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus. FEBS Lett 587(3):272–277PubMedCentralPubMedGoogle Scholar
  53. 53.
    Pan L, Yan J, Wu L, Zhang M (2009) Assembling stable hair cell tip link complex via multidentate interactions between harmonin and cadherin 23. Proc Natl Acad Sci USA 106(14):5575–5580PubMedCentralPubMedGoogle Scholar
  54. 54.
    Faure G, Revy P, Schertzer M, Londono-Vallejo A, Callebaut I (2013) The C-terminal extension of human RTEL1, mutated in Hoyeraal–Hreidarsson syndrome, contains Harmonin-N-like domains. Proteins. doi: 10.1002/prot.24438
  55. 55.
    Rosen JN, Sogah VM, Ye LY, Mably JD (2013) ccm2-like is required for cardiovascular development as a novel component of the Heg-CCM pathway. Dev Biol 376(1):74–85PubMedGoogle Scholar
  56. 56.
    Zheng X, Xu C, Smith AO, Stratman AN, Zou Z, Kleaveland B, Yuan L, Didiku C, Sen A, Liu X, Skuli N, Zaslavsky A, Chen M, Cheng L, Davis GE, Kahn ML (2012) Dynamic regulation of the cerebral cavernous malformation pathway controls vascular stability and growth. Dev Cell 23(2):342–355PubMedCentralPubMedGoogle Scholar
  57. 57.
    Voss K, Stahl S, Hogan BM, Reinders J, Schleider E, Schulte-Merker S, Felbor U (2009) Functional analyses of human and zebrafish 18-amino acid in-frame deletion pave the way for domain mapping of the cerebral cavernous malformation 3 protein. Hum Mutat 30(6):1003–1011PubMedGoogle Scholar
  58. 58.
    Li X, Zhang R, Zhang H, He Y, Ji W, Min W, Boggon TJ (2010) Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. J Biol Chem 285(31):24099–24107PubMedCentralPubMedGoogle Scholar
  59. 59.
    Ding J, Wang X, Li DF, Hu Y, Zhang Y, Wang DC (2010) Crystal structure of human programmed cell death 10 complexed with inositol-(1,3,4,5)-tetrakisphosphate: a novel adaptor protein involved in human cerebral cavernous malformation. Biochem Biophys Res Commun 399(4):587–592PubMedGoogle Scholar
  60. 60.
    Li X, Ji W, Zhang R, Folta-Stogniew E, Min W, Boggon TJ (2011) Molecular recognition of LD motifs by the FAT-homology domain of cerebral cavernous malformation 3 (CCM3). J Biol Chem 286(29):26138–26147PubMedCentralPubMedGoogle Scholar
  61. 61.
    Zhang M, Dong L, Shi Z, Jiao S, Zhang Z, Zhang W, Liu G, Chen C, Feng M, Hao Q, Wang W, Yin M, Zhao Y, Zhang L, Zhou Z (2013) Structural mechanism of CCM3 heterodimerization with GCKIII kinases. Structure 21(4):680–688PubMedGoogle Scholar
  62. 62.
    Xu X, Wang X, Zhang Y, Wang DC, Ding J (2013) Structural basis for the unique heterodimeric assembly between cerebral cavernous malformation 3 and germinal center kinase III. Structure 21(6):1059–1066PubMedGoogle Scholar
  63. 63.
    Hilder TL, Malone MH, Bencharit S, Colicelli J, Haystead TA, Johnson GL, Wu CC (2007) Proteomic identification of the cerebral cavernous malformation signaling complex. J Proteome Res 6(11):4343–4355PubMedGoogle Scholar
  64. 64.
    Costa B, Kean MJ, Ast V, Knight JD, Mett A, Levy Z, Ceccarelli DF, Badillo BG, Eils R, Konig R, Gingras AC, Fainzilber M (2012) STK25 protein mediates TrkA and CCM2 protein-dependent death in pediatric tumor cells of neural origin. J Biol Chem 287(35):29285–29289PubMedCentralPubMedGoogle Scholar
  65. 65.
    Stahl S, Gaetzner S, Voss K, Brackertz B, Schleider E, Surucu O, Kunze E, Netzer C, Korenke C, Finckh U, Habek M, Poljakovic Z, Elbracht M, Rudnik-Schoneborn S, Bertalanffy H, Sure U, Felbor U (2008) Novel CCM1, CCM2, and CCM3 mutations in patients with cerebral cavernous malformations: in-frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein complex. Hum Mutat 29(5):709–717PubMedGoogle Scholar
  66. 66.
    Kean MJ, Ceccarelli DF, Goudreault M, Sanches M, Tate S, Larsen B, Gibson LC, Derry WB, Scott IC, Pelletier L, Baillie GS, Sicheri F, Gingras AC (2011) Structure-function analysis of core STRIPAK proteins: a signaling complex implicated in Golgi polarization. J Biol Chem 286(28):25065–25075PubMedCentralPubMedGoogle Scholar
  67. 67.
    Berman JR, Kenyon C (2006) Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling. Cell 124(5):1055–1068PubMedGoogle Scholar
  68. 68.
    Frische EW, Zwartkruis FJ (2010) Rap1, a mercenary among the Ras-like GTPases. Dev Biol 340(1):1–9PubMedGoogle Scholar
  69. 69.
    Boettner B, Van Aelst L (2009) Control of cell adhesion dynamics by Rap1 signaling. Curr Opin Cell Biol 21(5):684–693PubMedCentralPubMedGoogle Scholar
  70. 70.
    Glading A, Han J, Stockton RA, Ginsberg MH (2007) KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J Cell Biol 179(2):247–254PubMedCentralPubMedGoogle Scholar
  71. 71.
    Liu JJ, Stockton RA, Gingras AR, Ablooglu AJ, Han J, Bobkov AA, Ginsberg MH (2011) A mechanism of Rap1-induced stabilization of endothelial cell–cell junctions. Mol Biol Cell 22(14):2509–2519PubMedCentralPubMedGoogle Scholar
  72. 72.
    Glading AJ, Ginsberg MH (2010) Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signaling. Dis Model Mech 3(1–2):73–83PubMedCentralPubMedGoogle Scholar
  73. 73.
    Faurobert E, Rome C, Lisowska J, Manet-Dupe S, Boulday G, Malbouyres M, Balland M, Bouin AP, Keramidas M, Bouvard D, Coll JL, Ruggiero F, Tournier-Lasserve E, Albiges-Rizo C (2013) CCM1-ICAP-1 complex controls beta1 integrin-dependent endothelial contractility and fibronectin remodeling. J Cell Biol 202(3):545–561PubMedCentralPubMedGoogle Scholar
  74. 74.
    Millon-Fremillon A, Brunner M, Abed N, Collomb E, Ribba AS, Block MR, Albiges-Rizo C, Bouvard D (2013) CaMKII-mediated intramolecular opening of integrin cytoplasmic domain associated protein-1 (ICAP-1alpha) negatively regulates beta1 integrins. J Biol Chem 288(28):20248–20260PubMedGoogle Scholar
  75. 75.
    Chang DD, Wong C, Smith H, Liu J (1997) ICAP-1, a novel beta1 integrin cytoplasmic domain-associated protein, binds to a conserved and functionally important NPXY sequence motif of beta1 integrin. J Cell Biol 138(5):1149–1157PubMedCentralPubMedGoogle Scholar
  76. 76.
    Zhang XA, Hemler ME (1999) Interaction of the integrin beta1 cytoplasmic domain with ICAP-1 protein. J Biol Chem 274(1):11–19PubMedGoogle Scholar
  77. 77.
    Calderwood DA, Tai V, Di Paolo G, De Camilli P, Ginsberg MH (2004) Competition for talin results in trans-dominant inhibition of integrin activation. J Biol Chem 279(28):28889–28895PubMedGoogle Scholar
  78. 78.
    Chang DD, Hoang BQ, Liu J, Springer TA (2002) Molecular basis for interaction between Icap1 alpha PTB domain and beta 1 integrin. J Biol Chem 277(10):8140–8145PubMedGoogle Scholar
  79. 79.
    Bouvard D, Vignoud L, Dupe-Manet S, Abed N, Fournier HN, Vincent-Monegat C, Retta SF, Fassler R, Block MR (2003) Disruption of focal adhesions by integrin cytoplasmic domain-associated protein-1 alpha. J Biol Chem 278(8):6567–6574PubMedGoogle Scholar
  80. 80.
    Brunner M, Millon-Fremillon A, Chevalier G, Nakchbandi IA, Mosher D, Block MR, Albiges-Rizo C, Bouvard D (2011) Osteoblast mineralization requires {beta}1 integrin/ICAP-1-dependent fibronectin deposition. J Cell Biol 194(2):307–322PubMedCentralPubMedGoogle Scholar
  81. 81.
    Millon-Fremillon A, Bouvard D, Grichine A, Manet-Dupe S, Block MR, Albiges-Rizo C (2008) Cell adaptive response to extracellular matrix density is controlled by ICAP-1-dependent beta1-integrin affinity. J Cell Biol 180(2):427–441PubMedCentralPubMedGoogle Scholar
  82. 82.
    Zawistowski JS, Serebriiskii IG, Lee MF, Golemis EA, Marchuk DA (2002) KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. Hum Mol Genet 11(4):389–396PubMedGoogle Scholar
  83. 83.
    Bouvard D, Aszodi A, Kostka G, Block MR, Albiges-Rizo C, Fassler R (2007) Defective osteoblast function in ICAP-1-deficient mice. Development 134(14):2615–2625PubMedCentralPubMedGoogle Scholar
  84. 84.
    Zhang J, Basu S, Rigamonti D, Dietz HC, Clatterbuck RE (2008) Krit1 modulates beta 1-integrin-mediated endothelial cell proliferation. Neurosurgery 63(3):571–578PubMedGoogle Scholar
  85. 85.
    Wustehube J, Bartol A, Liebler SS, Brutsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A (2010) Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci USA 107(28):12640–12645PubMedCentralPubMedGoogle Scholar
  86. 86.
    Brutsch R, Liebler SS, Wustehube J, Bartol A, Herberich SE, Adam MG, Telzerow A, Augustin HG, Fischer A (2010) Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis. Circ Res 107(5):592–601PubMedGoogle Scholar
  87. 87.
    You C, Sandalcioglu IE, Dammann P, Felbor U, Sure U, Zhu Y (2013) Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations. J Cell Mol Med 17(3):407–418PubMedGoogle Scholar
  88. 88.
    Hamada K, Shimizu T, Matsui T, Tsukita S, Hakoshima T (2000) Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain. EMBO J 19(17):4449–4462PubMedCentralPubMedGoogle Scholar
  89. 89.
    Lu TJ, Lai WY, Huang CY, Hsieh WJ, Yu JS, Hsieh YJ, Chang WT, Leu TH, Chang WC, Chuang WJ, Tang MJ, Chen TY, Lu TL, Lai MD (2006) Inhibition of cell migration by autophosphorylated mammalian sterile 20-like kinase 3 (MST3) involves paxillin and protein-tyrosine phosphatase-PEST. J Biol Chem 281(50):38405–38417PubMedGoogle Scholar
  90. 90.
    Ceccarelli DF, Laister RC, Mulligan VK, Kean MJ, Goudreault M, Scott IC, Derry WB, Chakrabartty A, Gingras AC, Sicheri F (2011) CCM3/PDCD10 heterodimerizes with germinal center kinase III (GCKIII) proteins using a mechanism analogous to CCM3 homodimerization. J Biol Chem 286(28):25056–25064PubMedCentralPubMedGoogle Scholar
  91. 91.
    Fidalgo M, Fraile M, Pires A, Force T, Pombo C, Zalvide J (2010) CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation. J Cell Sci 123(Pt 8):1274–1284PubMedGoogle Scholar
  92. 92.
    Preisinger C, Short B, De Corte V, Bruyneel E, Haas A, Kopajtich R, Gettemans J, Barr FA (2004) YSK1 is activated by the Golgi matrix protein GM130 and plays a role in cell migration through its substrate 14-3-3zeta. J Cell Biol 164(7):1009–1020PubMedCentralPubMedGoogle Scholar
  93. 93.
    Ling P, Lu TJ, Yuan CJ, Lai MD (2008) Biosignaling of mammalian Ste20-related kinases. Cell Signal 20(7):1237–1247PubMedGoogle Scholar
  94. 94.
    Zheng X, Xu C, Di Lorenzo A, Kleaveland B, Zou Z, Seiler C, Chen M, Cheng L, Xiao J, He J, Pack MA, Sessa WC, Kahn ML (2010) CCM3 signaling through sterile 20-like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations. J Clin Invest 120(8):2795–2804PubMedCentralPubMedGoogle Scholar
  95. 95.
    Richardson BT, Dibble CF, Borikova AL, Johnson GL (2013) Cerebral cavernous malformation is a vascular disease associated with activated RhoA signaling. Biol Chem 394(1):35–42PubMedCentralPubMedGoogle Scholar
  96. 96.
    Goudreault M, D’Ambrosio LM, Kean MJ, Mullin MJ, Larsen BG, Sanchez A, Chaudhry S, Chen GI, Sicheri F, Nesvizhskii AI, Aebersold R, Raught B, Gingras AC (2009) A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein. Mol Cell Proteomics 8(1):157–171PubMedCentralPubMedGoogle Scholar
  97. 97.
    Stockton RA, Shenkar R, Awad IA, Ginsberg MH (2010) Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity. J Exp Med 207(4):881–896PubMedCentralPubMedGoogle Scholar
  98. 98.
    Borikova AL, Dibble CF, Sciaky N, Welch CM, Abell AN, Bencharit S, Johnson GL (2010) Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype. J Biol Chem 285(16):11760–11764PubMedCentralPubMedGoogle Scholar
  99. 99.
    Uhlik MT, Abell AN, Johnson NL, Sun W, Cuevas BD, Lobel-Rice KE, Horne EA, Dell’Acqua ML, Johnson GL (2003) Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nat Cell Biol 5(12):1104–1110PubMedGoogle Scholar
  100. 100.
    Zhou X, Izumi Y, Burg MB, Ferraris JD (2011) Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-gamma1 to activation of the osmoprotective transcription factor NFAT5. Proc Natl Acad Sci USA 108(29):12155–12160PubMedCentralPubMedGoogle Scholar
  101. 101.
    Goitre L, Balzac F, Degani S, Degan P, Marchi S, Pinton P, Retta SF (2010) KRIT1 regulates the homeostasis of intracellular reactive oxygen species. PLoS ONE 5(7):e11786PubMedCentralPubMedGoogle Scholar
  102. 102.
    Guazzi P, Goitre L, Ferro E, Cutano V, Martino C, Trabalzini L, Retta SF (2012) Identification of the Kelch family protein Nd1-L as a novel molecular interactor of KRIT1. PLoS ONE 7(9):e44705PubMedCentralPubMedGoogle Scholar
  103. 103.
    Bacigaluppi S, Retta SF, Pileggi S, Fontanella M, Goitre L, Tassi L, La Camera A, Citterio A, Patrosso MC, Tredici G, Penco S (2013) Genetic and cellular basis of cerebral cavernous malformations: implications for clinical management. Clin Genet 83(1):7–14PubMedGoogle Scholar
  104. 104.
    Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G, Tournier-Lasserve E, Chapon F, Richichi C, Retta SF, Lampugnani MG, Dejana E (2013) EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498(7455):492–496PubMedGoogle Scholar
  105. 105.
    Zhang Y, Tang W, Zhang H, Niu X, Xu Y, Zhang J, Gao K, Pan W, Boggon TJ, Toomre D, Min W, Wu D (2013) A network of interactions enables CCM3 and STK24 to coordinate UNC13D-driven vesicle exocytosis in neutrophils. Dev Cell 27:215–226PubMedGoogle Scholar
  106. 106.
    Song Y, Eng M, Ghabrial AS (2013) Focal defects in single-celled tubes mutant for cerebral cavernous malformation 3, GCKIII, or NSF2. Dev Cell 25(5):507–519PubMedGoogle Scholar
  107. 107.
    Gunel M, Laurans MS, Shin D, DiLuna ML, Voorhees J, Choate K, Nelson-Williams C, Lifton RP (2002) KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein. Proc Natl Acad Sci USA 99(16):10677–10682PubMedCentralPubMedGoogle Scholar
  108. 108.
    Lampugnani MG, Orsenigo F, Rudini N, Maddaluno L, Boulday G, Chapon F, Dejana E (2010) CCM1 regulates vascular-lumen organization by inducing endothelial polarity. J Cell Sci 123(Pt 7):1073–1080PubMedGoogle Scholar
  109. 109.
    Fournier HN, Dupe-Manet S, Bouvard D, Luton F, Degani S, Block MR, Retta SF, Albiges-Rizo C (2005) Nuclear translocation of integrin cytoplasmic domain-associated protein 1 stimulates cellular proliferation. Mol Biol Cell 16(4):1859–1871PubMedCentralPubMedGoogle Scholar
  110. 110.
    Czubayko M, Knauth P, Schluter T, Florian V, Bohnensack R (2006) Sorting nexin 17, a non-self-assembling and a PtdIns(3)P high class affinity protein, interacts with the cerebral cavernous malformation related protein KRIT1. Biochem Biophys Res Commun 345(3):1264–1272PubMedGoogle Scholar
  111. 111.
    Brahme NN, Calderwood DA (2012) Cell adhesion: a FERM grasp of the tail sorts out integrins. Curr Biol 22(17):R692–R694PubMedGoogle Scholar
  112. 112.
    Bottcher RT, Stremmel C, Meves A, Meyer H, Widmaier M, Tseng HY, Fassler R (2012) Sorting nexin 17 prevents lysosomal degradation of beta1 integrins by binding to the beta1-integrin tail. Nat Cell Biol 14(6):584–592PubMedGoogle Scholar
  113. 113.
    Dibble CF, Horst JA, Malone MH, Park K, Temple B, Cheeseman H, Barbaro JR, Johnson GL, Bencharit S (2010) Defining the functional domain of programmed cell death 10 through its interactions with phosphatidylinositol-3,4,5-trisphosphate. PLoS ONE 5(7):e11740PubMedCentralPubMedGoogle Scholar
  114. 114.
    McDonald DA, Shi C, Shenkar R, Stockton RA, Liu F, Ginsberg MH, Marchuk DA, Awad IA (2012) Fasudil decreases lesion burden in a murine model of cerebral cavernous malformation disease. Stroke 43(2):571–574PubMedCentralPubMedGoogle Scholar
  115. 115.
    Li DY, Whitehead KJ (2010) Evaluating strategies for the treatment of cerebral cavernous malformations. Stroke 41(10 Suppl):S92–S94PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  1. 1.Department of PharmacologyYale University School of MedicineNew HavenUSA
  2. 2.Yale Cancer CenterYale University School of MedicineNew HavenUSA

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