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PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations

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Abstract

Cerebral cavernous malformations (CCM) are common vascular malformation of the brain and are associated with abnormal angiogenesis. Although the exact etiology and the underlying molecular mechanism are still under investigation, recent advances in the identification of the mutations in three genes and their interactions with different signaling pathways have shed light on our understanding of CCM pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression. Here, we provide an update literature review on the current knowledge of the PTEN/PI3K/Akt/VEGF signaling in angiogenesis, more importantly in CCM pathogenesis. In addition to reviewing the current literatures, this article will also focus on the structural domain of the three CCM proteins and their interacting partners. Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment.

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References

  1. Batra S, Lin D, Recinos PF, Zhang J, Rigamonti D (2009) Cavernous malformations: natural history, diagnosis and treatment. Nat Rev Neurol 5(12):659–670

    Article  PubMed  Google Scholar 

  2. 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, N. Societe Francaise de (2005) Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 76(1):42–51

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Bertalanffy H, Benes L, Miyazawa T, Alberti O, Siegel AM, Sure U (2002) Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients. Neurosurg Rev 25(1–2):1–53, discussion 54–55

    Article  PubMed  Google Scholar 

  4. Bertalanffy H, Kuhn G, Scheremet R, Seeger W (1992) Indications for surgery and prognosis in patients with cerebral cavernous angiomas. Neurol Med Chir (Tokyo) 32(9):659–666

    Article  CAS  Google Scholar 

  5. Brazil DP, Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26(11):657–664

    Article  CAS  PubMed  Google Scholar 

  6. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296(5573):1655–1657

    Article  CAS  PubMed  Google Scholar 

  7. 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):1871–1881

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Choorapoikayil S, Weijts B, Kers R, de Bruin A, den Hertog J (2013) Loss of Pten promotes angiogenesis and enhanced vegfaa expression in zebrafish. Dis Model Mech 6(5):1159–1166

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Cortes Vela JJ, Concepcion Aramendia L, Ballenilla Marco F, Gallego Leon JI, Gonzalez-Spinola San Gil J (2012) Cerebral cavernous malformations: spectrum of neuroradiological findings. Radiol 54(5):401–409

    CAS  Google Scholar 

  10. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87(7):1161–1169

    Article  CAS  PubMed  Google Scholar 

  11. 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):e11740

    Article  PubMed Central  PubMed  Google Scholar 

  12. Draheim KM, Fisher OS, Boggon TJ, Calderwood DA (2014) Cerebral cavernous malformation proteins at a glance. J Cell Sci 127(Pt 4):701–707

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. 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):453–458

    Article  CAS  PubMed  Google Scholar 

  14. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619

    Article  CAS  PubMed  Google Scholar 

  15. 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):1274–1284

    Article  CAS  PubMed  Google Scholar 

  16. Fischer A, Zalvide J, Faurobert E, Albiges-Rizo C, Tournier-Lasserve E (2013) Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis. Trends Mol Med 19(5):302–308

    Article  CAS  PubMed  Google Scholar 

  17. Fisher OS, Boggon TJ (2014) Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology. Cell Mol Life Sci 71(10):1881–1892

    Article  CAS  PubMed  Google Scholar 

  18. 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):272–277

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Georgescu MM, Kirsch KH, Akagi T, Shishido T, Hanafusa H (1999) The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci U S A 96(18):10182–10187

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Gingras AR, Liu JJ, Ginsberg MH (2012) Structural basis of the junctional anchorage of the cerebral cavernous malformations complex. J Cell Biol 199(1):39–48

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. 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):23639–23649

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. 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):247–254

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Gunel M, Awad IA, Anson J, Lifton RP (1995) Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21. Proc Natl Acad Sci U S A 92(14):6620–6624

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. 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 U S A 99(16):10677–10682

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Haasdijk RA, Cheng C, Maat-Kievit AJ, Duckers HJ (2012) Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management. Eur J Hum Genet 20(2):134–140

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Hamada K, Sasaki T, Koni PA, Natsui M, Kishimoto H, Sasaki J, Yajima N, Horie Y, Hasegawa G, Naito M, Miyazaki J, Suda T, Itoh H, Nakao K, Mak TW, Nakano T, Suzuki A (2005) The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes Dev 19(17):2054–2065

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. 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):585–591

    Article  CAS  PubMed  Google Scholar 

  28. He Y, Zhang H, Yu L, Gunel M, Boggon TJ, Chen H, Min W (2010) Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Sci Signal 3(116):ra26

    Article  PubMed Central  PubMed  Google Scholar 

  29. Hemmings BA, Restuccia DF (2012) PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol 4(9):a011189

    Article  PubMed Central  PubMed  Google Scholar 

  30. Huang J, Kontos CD (2002) PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects. J Biol Chem 277(13):10760–10766

    Article  CAS  PubMed  Google Scholar 

  31. Hwang J, Pallas DC (2014) STRIPAK complexes: structure, biological function, and involvement in human diseases. Int J Biochem Cell Biol 47:118–148

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Jakimovski, D., H. Schneider, K. Frei, L. N. Kennes and H. Bertalanffy (2014). Bleeding propensity of cavernous malformations: impact of tight junction alterations on the occurrence of overt hematoma. J Neurosurg: 1–8

  33. Jiang BH, Liu LZ (2009) PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res 102:19–65

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Johnson EW, Iyer LM, Rich SS, Orr HT, Gil-Nagel A, Kurth JH, Zabramski JM, Marchuk DA, Weissenbach J, Clericuzio CL, Davis LE, Hart BL, Gusella JF, Kosofsky BE, Louis DN, Morrison LA, Green ED, Weber JL (1995) Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig. Genome Res 5(4):368–380

    Article  CAS  PubMed  Google Scholar 

  35. Jones N, Master Z, Jones J, Bouchard D, Gunji Y, Sasaki H, Daly R, Alitalo K, Dumont DJ (1999) Identification of Tek/Tie2 binding partners. Binding to a multifunctional docking site mediates cell survival and migration. J Biol Chem 274(43):30896–30905

    Article  CAS  PubMed  Google Scholar 

  36. Kini V, Chavez A, Mehta D (2010) A new role for PTEN in regulating transient receptor potential canonical channel 6-mediated Ca2+ entry, endothelial permeability, and angiogenesis. J Biol Chem 285(43):33082–33091

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. 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):169–176

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Labauge P, Denier C, Bergametti F, Tournier-Lasserve E (2007) Genetics of cavernous angiomas. Lancet Neurol 6(3):237–244

    Article  CAS  PubMed  Google Scholar 

  39. Leblanc GG, Golanov E, Awad IA, Young WL, N. W. C. Biology of Vascular Malformations of the Brain (2009) Biology of vascular malformations of the brain. Stroke 40(12):e694–e702

    Article  PubMed Central  PubMed  Google Scholar 

  40. Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP (1999) Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99(3):323–334

    Article  CAS  PubMed  Google Scholar 

  41. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275(5308):1943–1947

    Article  CAS  PubMed  Google Scholar 

  42. 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):24099–24107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16(1):64–67

    Article  CAS  PubMed  Google Scholar 

  44. Lin C, Meng S, Zhu T, Wang X (2010) PDCD10/CCM3 acts downstream of {gamma}-protocadherins to regulate neuronal survival. J Biol Chem 285(53):41675–41685

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. 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):1459–1464

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Liquori CL, Berg MJ, Squitieri F, Ottenbacher M, Sorlie M, Leedom TP, Cannella M, Maglione V, Ptacek L, Johnson EW, Marchuk DA (2006) Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat 27(1):118

    Article  PubMed  Google Scholar 

  47. 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):2509–2519

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. 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):719–729

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273(22):13375–13378

    Article  CAS  PubMed  Google Scholar 

  50. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277(5322):55–60

    Article  CAS  PubMed  Google Scholar 

  51. Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ, Eng C (1997) Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet 16(4):333–334

    Article  CAS  PubMed  Google Scholar 

  52. Mathiesen T, Edner G, Kihlstrom L (2003) Deep and brainstem cavernomas: a consecutive 8-year series. J Neurosurg 99(1):31–37

    Article  PubMed  Google Scholar 

  53. Meng G, Bai C, Yu T, Wu Z, Liu X, Zhang J, Zhao J (2014) The association between cerebral developmental venous anomaly and concomitant cavernous malformation: an observational study using magnetic resonance imaging. BMC Neurol 14:50

    Article  PubMed Central  PubMed  Google Scholar 

  54. Ng I, Tan WL, Ng PY, Lim J (2005) Hypoxia inducible factor-1alpha and expression of vascular endothelial growth factor and its receptors in cerebral arteriovenous malformations. J Clin Neurosci 12(7):794–799

    Article  CAS  PubMed  Google Scholar 

  55. Park JH, Lee JY, Shin DH, Jang KS, Kim HJ, Kong G (2011) Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1alpha mediated by the PTEN/PI3K/Akt pathway. Oncogene 30(45):4578–4589

    Article  CAS  PubMed  Google Scholar 

  56. Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA (2013) PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol Cell Biol 33(16):3091–3098

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Pearson MA, Reczek D, Bretscher A, Karplus PA (2000) Structure of the ERM protein moesin reveals the FERM domain fold masked by an extended actin binding tail domain. Cell 101(3):259–270

    Article  CAS  PubMed  Google Scholar 

  58. 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):1070–1075

    Article  CAS  PubMed  Google Scholar 

  59. 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):74–85

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. 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):123–126

    Article  CAS  PubMed  Google Scholar 

  61. 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):2325–2333

    Article  CAS  PubMed  Google Scholar 

  62. Samii M, Eghbal R, Carvalho GA, Matthies C (2001) Surgical management of brainstem cavernomas. J Neurosurg 95(5):825–832

    Article  CAS  PubMed  Google Scholar 

  63. Scheid MP, Woodgett JR (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2(10):760–768

    Article  CAS  PubMed  Google Scholar 

  64. Schneider H, Errede M, Ulrich NH, Virgintino D, Frei K, Bertalanffy H (2011) Impairment of tight junctions and glucose transport in endothelial cells of human cerebral cavernous malformations. J Neuropathol Exp Neurol 70(6):417–429

    Article  CAS  PubMed  Google Scholar 

  65. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732

    Article  CAS  PubMed  Google Scholar 

  66. Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13(5):283–296

    CAS  PubMed  Google Scholar 

  67. 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):709–717

    Article  CAS  PubMed  Google Scholar 

  68. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15(4):356–362

    Article  CAS  PubMed  Google Scholar 

  69. Sugden PH, McGuffin LJ, Clerk A (2013) SOcK, MiSTs, MASK and STicKs: the GCKIII (germinal centre kinase III) kinases and their heterologous protein-protein interactions. Biochem J 454(1):13–30

    Article  CAS  PubMed  Google Scholar 

  70. Sure U, Battenberg E, Dempfle A, Tirakotai W, Bien S, Bertalanffy H (2004) Hypoxia-inducible factor and vascular endothelial growth factor are expressed more frequently in embolized than in nonembolized cerebral arteriovenous malformations. Neurosurgery 55(3):663–669, discussion 669–670

    Article  PubMed  Google Scholar 

  71. Sure U, Butz N, Schlegel J, Siegel AM, Wakat JP, Mennel HD, Bien S, Bertalanffy H (2001) Endothelial proliferation, neoangiogenesis, and potential de novo generation of cerebrovascular malformations. J Neurosurg 94(6):972–977

    Article  CAS  PubMed  Google Scholar 

  72. Tian T, Nan KJ, Wang SH, Liang X, Lu CX, Guo H, Wang WJ, Ruan ZP (2010) PTEN regulates angiogenesis and VEGF expression through phosphatase-dependent and -independent mechanisms in HepG2 cells. Carcinogenesis 31(7):1211–1219

    Article  PubMed  Google Scholar 

  73. Tsigkos S, Zhou Z, Kotanidou A, Fulton D, Zakynthinos S, Roussos C, Papapetropoulos A (2006) Regulation of Ang2 release by PTEN/PI3-kinase/Akt in lung microvascular endothelial cells. J Cell Physiol 207(2):506–511

    Article  CAS  PubMed  Google Scholar 

  74. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 11(5):329–341

    Article  CAS  PubMed  Google Scholar 

  75. 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):1003–1011

    Article  CAS  PubMed  Google Scholar 

  76. 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):249–256

    Article  CAS  PubMed  Google Scholar 

  77. Wen S, Stolarov J, Myers MP, Su JD, Wigler MH, Tonks NK, Durden DL (2001) PTEN controls tumor-induced angiogenesis. Proc Natl Acad Sci U S A 98(8):4622–4627

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Weng LP, Smith WM, Dahia PL, Ziebold U, Gil E, Lees JA, Eng C (1999) PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. Cancer Res 59(22):5808–5814

    CAS  PubMed  Google Scholar 

  79. 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):177–184

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. 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):407–418

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Zhang J, Clatterbuck RE, Rigamonti D, Dietz HC (2000) Mutations in KRIT1 in familial cerebral cavernous malformations. Neurosurgery 46(5):1272–1277, discussion 1277–1279

    Article  CAS  PubMed  Google Scholar 

  82. 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):353–359, discussion 359

    Article  PubMed  Google Scholar 

  83. Zhao Y, Tan YZ, Zhou LF, Wang HJ, Mao Y (2007) Morphological observation and in vitro angiogenesis assay of endothelial cells isolated from human cerebral cavernous malformations. Stroke 38(4):1313–1319

    Article  PubMed  Google Scholar 

  84. 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):342–355

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Zhou HJ, Tang T, Cui HJ, Yang AL, Luo JK, Lin Y, Yang QD, Li XQ (2012) Thrombin-triggered angiogenesis in rat brains following experimental intracerebral hemorrhage. J Neurosurg 117(5):920–928

    Article  CAS  PubMed  Google Scholar 

  86. Zhou XP, Marsh DJ, Hampel H, Mulliken JB, Gimm O, Eng C (2000) Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum Mol Genet 9(5):765–768

    Article  CAS  PubMed  Google Scholar 

  87. Zhu Y, Wloch A, Wu Q, Peters C, Pagenstecher A, Bertalanffy H, Sure U (2009) Involvement of PTEN promoter methylation in cerebral cavernous malformations. Stroke 40(3):820–826

    Article  CAS  PubMed  Google Scholar 

  88. Zhu Y, Wu Q, Fass M, Xu JF, You C, Muller O, Sandalcioglu IE, Zhang JM, Sure U (2011) In vitro characterization of the angiogenic phenotype and genotype of the endothelia derived from sporadic cerebral cavernous malformations. Neurosurgery 69(3):722–731, discussion 731–722

    Article  PubMed  Google Scholar 

  89. Zhu Y, Wu Q, Xu JF, Miller D, Sandalcioglu IE, Zhang JM, Sure U (2010) Differential angiogenesis function of CCM2 and CCM3 in cerebral cavernous malformations. Neurosurg Focus 29(3):E1

    Article  PubMed  Google Scholar 

  90. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 14(4):391–396

    PubMed Central  CAS  PubMed  Google Scholar 

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  1. International Neuroscience Institute, Rudolf-Pichlmayr-Straße 4, 30625, Hannover, Germany

    Souvik Kar, Amir Samii & Helmut Bertalanffy

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  1. Souvik Kar
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  2. Amir Samii
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  3. Helmut Bertalanffy
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Correspondence to Souvik Kar.

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Christian Hartmann, Hannover, Germany

The insights in the underlying molecular mechanisms driving cerebral cavernous malformations dramatically increased over the last few years, shifting our understanding to a point that even the name of the lesion has to be critically reviewed. The first big step was the identification of mutations in the genes CCM1, CCM2, and CCM3 in the vast majority of patients with familial cerebral cavernous malformations who develop multiple lesions [1–5]. Nearly all mutations in the CCM1-3 genes resulted in a premature terminated protein with a loss of function as consequence (reviewed in [6]). Such pattern indicated a tumor suppressor gene “two hit” mechanism and, indeed, a first early report reported the case of an identical biallelic germline and somatic CCM1 mutation [7]. However, the next big step was the systematical analysis of this biallelic “two hit” knock-out mechanism by Amy Akers and coworkers who identified by using a sophisticated strategy for all three CCM genes in many cases a germline mutation in all cells of the body and a second, so-called somatic mutation solely in a fraction of the endothelial cells of a specific cerebral cavernous malformation [8]. Furthermore, they identified the somatic mutations only in endothelial cells, thereby delineating this tissue component of cerebral cavernous malformations to be the driving one. In summary, all these data bring up the question if cerebral cavernous lesions are “malformations” or if it would be more appropriate to move them to the group of benign vascular tumors—and include them in the upcoming WHO classification of brain tumors.

In oncology, the next step after establishing the genetic background is to functionally characterize the consequences of the driving forces. In line with this notion, the review presented here by Souvik Kar and coworkers sheds light on current knowledge regarding the CCM1-3 proteins and their potential cross talk with the PTEN/PI3K/Akt/VEGF signaling pathway that has been well characterized in many neoplasms. The reviewed protein functions open up various opportunities for upcoming research projects.

Still the cerebral cavernous malformation research is hampered by the very low number of “neoplastic” cells within such lesions. Conventional approaches fail in many ways to go ahead. Presumably massive parallel sequencing will allow determining the somatic mutational status of the CCM1-3 genes in a much faster ways than by methods the group by Amy Akers used [8]. Such next generation sequencing approach may even help to identify CCM1-3 biallelic mutations in sporadic cases of cerebral cavernous malformations. The currently available CCM1/2 knock-out mouse models unfortunately generated not too many functional insights in the disease [9, 10]. Maybe it would instead be worth using one of the established endothelial cell system models to knock-in biallelic CCM1-3 mutations. This way simple expression array studies should generate data about up- and downregulated genes due to the functional loss of CCM1-3 gene products. Furthermore, the chances are given to identify specifically upregulated genes so—in a best setting—the particular CCM1, CCM2, or CCM3 subtype might become determinable by simple immunohistochemistry-based surrogate markers. Having such simple assay correlation studies between the particular genotype and morphology and/or clinical phenotype should become achievable. Next, such CCM1-3 knock-in endothelial cell system model would allow studies of altered protein-protein interactions and transformed signaling pathways. Finally, understanding of deregulated signaling pathways might lead to drug therapies for those patients suffering from cerebral cavernous malformations that cannot be cured by surgery alone.

Yuan Zhu, Ulrich Sure, Essen, Germany

Cerebral cavernous malformation (CCM), classified as sporadic and familial (inherited) forms, is one of the most common cerebral vascular anomalies involving aberrant angiogenesis. Although familial CCM (fCCM) accounts for only around 20 % of CCM, a recent study by Spiegler et al. (Mol Genetics & Genomic Med 2014) has shown that the mutation detection rate of CCM1 (60 %), CCM2 (18 %), and CCM3 (22 %) in fCCM is much higher than previous thought; moreover, increasing evidence indicates more aggressive features, e.g., often presence of multiple lesions, earlier onset, and increased hemorrhage rate, in fCCM than in sporadic CCM. In view of the literature, researchers have put much attention to study the angiogenic function and the underlying signaling pathways of CCM proteins during the last decade, which has significantly improved our understanding on the pathogenesis of CCM. The present review has outlined the structure and the function of three CCM proteins, highlighting the protein-protein interaction at the molecular structure basis. Differently from other recent review articles, Kar and his colleagues have identified not only the key advances of current understandings on the signaling pathways related to the common or distinct functions of three CCM proteins but further emphasized the PTEN/PI3k/Akt/VEGF signaling in CCM. PTEN deficiency due to its mutation or epigenetic alterations leads to the activation of PI3k/Akt signaling, which in turn activates VEGF pathway and subsequently stimulates angiogenesis. Despite of the well-defined central role of this pathway in the angiogenesis of various human cancers, it is just recently implicated in CCM and it is an obviously important part of the pathomechanism of CCM. PTEN DNA promoter methylation is rarely seen in normal tissues, but PTEN deficiency due to its promoter methylation was detected by our group in 15.9 % of a series of 69 CCM, in 5 of 6 fCCM and in 46.7 % of CCMs with multiple lesions (Zhu et al.; Stroke 2009). These data point out that it is worthwhile to further characterize PTEN DNA promoter methylation and the downstream pathways in a large series of fCCM. As concluded by Kar and his colleagues in this review, PTEN/PI3k/Akt/VEGF signaling together with other identified pathways may simultaneously contribute to the pathomechanisms of CCM.

References

1. Bergametti, F., et al., Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet, 2005. 76 (1): p. 42–51.

2. Denier, C., et al., Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet, 2004. 74 (2): p. 326–37.

3. Laberge-le Couteulx, S., et al., Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet, 1999. 23 (2): p. 189–93.

4. Liquori, C.L., 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 (6): p. 1459–64.

5. Sahoo, T., et al., Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet, 1999. 8 (12): p. 2325–33.

6. Riant, F., et al., Recent insights into cerebral cavernous malformations: the molecular genetics of CCM. FEBS J, 2010. 277 (5): p. 1070–5.

7. Gault, J., et al., Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke, 2005. 36 (4): p. 872–4.

8. Akers, A.L., et al., Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum Mol Genet, 2009. 18 (5): p. 919–30.

9. Plummer, N.W., et al., Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous malformations. Mamm Genome, 2006. 17 (2): p. 119–28.

10. Whitehead, K.J., et al., Ccm1 is required for arterial morphogenesis: implications for the etiology of human cavernous malformations. Development, 2004. 131 (6): p. 1437–48.

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Kar, S., Samii, A. & Bertalanffy, H. PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev 38, 229–237 (2015). https://doi.org/10.1007/s10143-014-0597-8

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