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  • Print publication year: 2011
  • Online publication date: September 2011

Chapter 5 - Molecular biology of cerebral cavernous malformation

from Section 1 - Biology
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Cavernous Malformations of the Nervous System
  • Online ISBN: 9781139003636
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1. Laberge-le Couteulx, S., Jung, H. H., et al. Truncating mutations in CCM1, encoding KRIT1, cause hereditarycavernous angiomas. Nat Genet 1999;23:189–193.
2. Sahoo, T., Johnson, E. W., et al. Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 1999;8:2325–2333.
3. Eerola, I., Plate, K. H., et al. KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation. Hum Mol Genet 2000;9:1351–1355.
4. Zhang, J., Clatterbuck, R. E., et al. Cloning of the murine Krit1 cDNA reveals novel mammalian 5′ coding exons. Genomics 2000;70:392–395.
5. Liquori, C. L., Berg, M. J., et al. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 2003;73:1459–1464.
6. Bergametti, F., Denier, C., et al. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 2005;76:42–51.
7. Batra, S., Lin, D., et al. Cavernous malformations: natural history, diagnosis and treatment. Nat Rev Neurol 2009;659–670.
8. Zawistowski, J. S., Stalheim, L., et al. CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet 2005;14:2521–2531.
9. Hilder, T. L., Malone, M. H., et al. Proteomic identification of the cerebral cavernous malformation signaling complex. J Proteome Res 2007;6:4343–4355.
10. Voss, K., Stahl, S., et al. CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. Neurogenetics 2007;8:249–256.
11. Zhang, J., Rigamonti, D., et al. Interaction between krit1 and malcavernin: implications for the pathogenesis of cerebral cavernous malformations. Neurosurgery 2007;60:353–359; discussion 359.
12. Marcos Toledano, M. M., Portilla Cuenca, J. C., et al. [Pseudo-emesis gravidarum caused by complicated cerebral venous angioma]. Neurologia 2006;21:92–95.
13. Seker, A., Pricola, K. L., et al. CCM2 expression parallels that of CCM1. Stroke 2006;37:518–523.
14. Zhang, J., Basu, S., et al. Pathogenesis of cerebral cavernous malformation: Depletion of Krit1 leads to perturbation of 1 integrin-mediated endothelial cell mobility and survival. Am J Hum Genet 2004;suppl:S222.
15. Zhang, J., Clatterbuck, R. E., et al. Interaction between krit1 and icap1alpha infers perturbation of integrin beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation. Hum Mol Genet 2001;10:2953–2960.
16. Serebriiskii, I., Estojak, J., et al. Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21–22. Oncogene 1997;15:1043–1049.
17. Zawistowski, J. S., Serebriiskii, I. G., et al. KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. Hum Mol Genet 2002;11:389–396.
18. Wang, Y. G., Liu, H. T., et al. cDNA cloning and expression of an apoptosis-related gene, human TFAR-15 gene. Science in China C Life Sci 1999;:331–336.
19. Kim, D. G., Choe, W. J., et al. Radiosurgery of intracranial cavernous malformations. Acta Neurochir (Wien) 2002;144:869–878; discussion 878.
20. Chang, D. D., Wong, C., et al. 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 1997;138:1149–1157.
21. Glading, A., Han, J., et al. KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions. J Cell Biol 2007;179:247–254.
22. Beraud-Dufour, S., Gautier, R., et al. Krit 1 interactions with microtubules and membranes are regulated by Rap1 and integrin cytoplasmic domain associated protein-1. FEBS J 2007;274:5518–5532.
23. Gunel, M., Laurans, M. S., et al. KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein. Proc Natl Acad Sci USA 2002;99:10677–10682.
24. Czubayko, M., Knauth, P., et al. 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 2006;345:1264–1272.
25. Uhlik, M. T., Abell, A. N., et al. Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nat Cell Biol 2003;5:1104–1110.
26. Hilder, T. L., Malone, M. H., et al. Hyperosmotic induction of mitogen-activated protein kinase scaffolding. Methods Enzymol 2007;428:297–312.
27. Ma, X., Zhao, H., et al. PDCD10 interacts with Ste20-related kinase MST4 to promote cell growth and transformation via modulation of the ERK pathway. Mol Biol Cell 2007;18:1965–1978.
28. Rual, J. F., Venkatesan, K., et al. Towards a proteome-scale map of the human protein-protein interaction network. Nature 2005;437:1173–1178.
29. Ewing, R. M., Chu, P., et al. Large-scale mapping of human protein-protein interactions by mass spectrometry. Mol Syst Biol 2007;3:89.
30. Goudreault, M., D’Ambrosio, L. M., et al. 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 2009;8:157–171.
31. Eerola, I., McIntyre, B., et al. Identification of eight novel 5′-exons in cerebral capillary malformation gene-1 (CCM1) encoding KRIT1. Biochim Biophys Acta 2001;1517:464–467.
32. Sahoo, T., Goenaga-Diaz, E., et al. Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene. Genomics 2001;71:123–126.
33. Zawistowski, J. S., Uhlik, M. T., et al. Interaction of the Cerebral Cavernous Malformations type 1 and 2 gene products. Am J Hum Genet 2004;suppl:S60.
34. Zhang, J., Basu, S., et al. krit1 modulates beta1-integrin-mediated endothelial cell proliferation. Neurosurgery 2008;63:571–578; discussion 578.
35. Schlaepfer, D. D. & Hunter, T.Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem 1997;272:13189–13195.
36. Arthur, W. T., Noren, N. K., et al. Regulation of Rho family GTPases by cell-cell and cell-matrix adhesion. Biol Res 2002;35:239–246.
37. Davis, G. E., Bayless, K. J., et al. Molecular basis of endothelial cell morphogenesis in three-dimensional extracellular matrices. Anat Rec 2002;268:252–275.
38. Degani, S., Balzac, F., et al. The integrin cytoplasmic domain-associated protein ICAP-1 binds and regulates Rho family GTPases during cell spreading. J Cell Biol 2002;156:377–388.
39. Bouvard, D., Vignoud, L., et al. Disruption of focal adhesions by integrin cytoplasmic domain-associated protein-1 alpha. J Biol Chem 2003;278:6567–6574.
40. Zhang, J., Clatterbuck, R. E., et al. New insight of the molecular pathogenesis of CCM. The 1st international workshop on the pathogenesis of cerebral cavernous malformation. Duke, North Carolina, 2005.
41. Bahary, N., Goishi, K., et al. Duplicate VegfA genes and orthologues of the KDR receptor tyrosine kinase family mediate vascular development in the zebrafish. Blood 2007;110:3627–3636.
42. Harel, L., Costa, B., et al. CCM2 mediates death signaling by the TrkA receptor tyrosine kinase. Neuron 2009;63:585–591.
43. Gruber-Olipitz, M. & Segal, R. A.Live or let die: CCM2 provides the link. Neuron 2009;63:559–560.
44. Tanriover, G., Boylan, A. J., et al. PDCD10, the gene mutated in cerebral cavernous malformation 3, is expressed in the neurovascular unit. Neurosurgery 2008;62:930–938; discussion 938.
45. Chen, L., Tanriover, G., et al. Apoptotic functions of PDCD10/CCM3, the gene mutated in cerebral cavernous malformation 3. Stroke 2009;40:1474–1481.
46. Lin, J. L., Chen, H. C., et al. MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway. Oncogene 2001;20:6559–6569.
47. Chen, J. N., Haffter, P., et al. Mutations affecting the cardiovascular system and other internal organs in zebrafish. Development 1996;123:293–302.
48. Stainier, D. Y., Fouquet, B., et al. Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo. Development 1996;123:285–292.
49. Mably, J. D., Chuang, L. P., et al. Santa and valentine pattern concentric growth of cardiac myocardium in the zebrafish. Development 2006;133:3139–3146.
50. Hogan, B. M., Bussmann, J., et al. Ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish. Hum Mol Genet 2008;17:2424–2432.
51. Whitehead, K. J., Plummer, N. W., et al. Ccm1 is required for arterial morphogenesis: implications for the etiology of human cavernous malformations. Development 2004;131:1437–1448.
52. Jin, S.-W., Herzog, W., et al. A transgene-assisted genetic screen identifies essential regulators of vascular development in vertebrate embryos. Dev Biol 2007;307:29–42.
53. Kleaveland, B., Zheng, X., et al. Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway. Nat Med 2009;15:169–176.
54. Whitehead, K. J., Chan, A. C., et al. The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med 2009;15:177–184.
55. Liu, H. L., Rigamonti, D., et al. CCM1 plays essential role in b-integrin-mediated endothelial cell integrity. Translational Stroke Res 2010.
56. Voss, K., Stahl, S., et al. 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 2009;30:1003–1011.