neurofibromin 1


Summary: A protein found most abundantly in the nervous system. Defects or deficiencies in this protein are associated with NEUROFIBROMATOSIS 1, Watson syndrome, and LEOPARD syndrome. Mutations in the gene (GENE, NEUROFIBROMATOSIS 1) affect two known functions: regulation of ras-GTPase and tumor suppression.

Top Publications

  1. Sharma M, Zehnbauer B, Watson M, Gutmann D. RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma. Neurology. 2005;65:1335-6 pubmed
  2. Yan J, Chen S, Zhang Y, Li X, Li Y, Wu X, et al. Rac1 mediates the osteoclast gains-in-function induced by haploinsufficiency of Nf1. Hum Mol Genet. 2008;17:936-48 pubmed
    ..Collectively, these data demonstrate that Rac1 critically contributes to increased osteoclast function induced by haploinsufficiency of Nf1 and implicate Rac1 as a rational therapeutic target for osteoporosis. ..
  3. Hannan F, Ho I, Tong J, Zhu Y, Nurnberg P, Zhong Y. Effect of neurofibromatosis type I mutations on a novel pathway for adenylyl cyclase activation requiring neurofibromin and Ras. Hum Mol Genet. 2006;15:1087-98 pubmed
    ..Further, we demonstrate that sequences in the C-terminal region of hNF1 are sufficient for NF1/Galpha(s)-dependent neurotransmitter stimulated AC activity, and for rescue of body size defects in Nf1 mutant flies. ..
  4. Elefteriou F, Benson M, Sowa H, Starbuck M, Liu X, Ron D, et al. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab. 2006;4:441-51 pubmed
    ..By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development...
  5. Ferner R, Huson S, Thomas N, Moss C, Willshaw H, Evans D, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44:81-8 pubmed
    ..The consensus statement discusses the diagnostic criteria, major differential diagnoses, clinical manifestations and the present strategies for monitoring and management of NF1 complications. ..
  6. Hegedus B, Dasgupta B, Shin J, Emnett R, Hart Mahon E, Elghazi L, et al. Neurofibromatosis-1 regulates neuronal and glial cell differentiation from neuroglial progenitors in vivo by both cAMP- and Ras-dependent mechanisms. Cell Stem Cell. 2007;1:443-57 pubmed publisher
    ..Together, these findings demonstrate that neurofibromin is required for normal glial and neuronal development involving separable Ras-dependent and cAMP-dependent mechanisms. ..
  7. Harashima T, Anderson S, Yates J, Heitman J. The kelch proteins Gpb1 and Gpb2 inhibit Ras activity via association with the yeast RasGAP neurofibromin homologs Ira1 and Ira2. Mol Cell. 2006;22:819-30 pubmed
    ..Because the Gpb1/2 binding domain on Ira1/2 is conserved in the human neurofibromin protein, an analogous signaling network may contribute to the neoplastic development of neurofibromatosis type 1. ..
  8. Johannessen C, Reczek E, James M, Brems H, Legius E, Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A. 2005;102:8573-8 pubmed
    ..Finally, these data suggest that rapamycin, or its derivatives, may represent a viable therapy for NF1. ..
  9. Ozawa T, Araki N, Yunoue S, Tokuo H, Feng L, Patrakitkomjorn S, et al. The neurofibromatosis type 1 gene product neurofibromin enhances cell motility by regulating actin filament dynamics via the Rho-ROCK-LIMK2-cofilin pathway. J Biol Chem. 2005;280:39524-33 pubmed
    ..These findings may explain, in part, the mechanism of multiple neurofibroma formation in NF1 patients. ..

More Information


  1. Chai G, Liu N, Ma J, Li H, Oblinger J, Prahalad A, et al. MicroRNA-10b regulates tumorigenesis in neurofibromatosis type 1. Cancer Sci. 2010;101:1997-2004 pubmed publisher
    ..These results suggest that miR-10b may play an important role in NF1 tumorigenesis through targeting neurofibromin and RAS signaling. ..
  2. Munchhof A, Li F, White H, Mead L, Krier T, Fenoglio A, et al. Neurofibroma-associated growth factors activate a distinct signaling network to alter the function of neurofibromin-deficient endothelial cells. Hum Mol Genet. 2006;15:1858-69 pubmed
    ..Thus, these studies identify a unique biochemical pathway in Nf1+/- ECs as a potential therapeutic target in the neurofibroma microenvironment...
  3. Sangha N, Wu R, Kuick R, Powers S, Mu D, Fiander D, et al. Neurofibromin 1 (NF1) defects are common in human ovarian serous carcinomas and co-occur with TP53 mutations. Neoplasia. 2008;10:1362-72, following 1372 pubmed
  4. McClatchey A. Neurofibromatosis. Annu Rev Pathol. 2007;2:191-216 pubmed
    ..An important outcome of the study of neurofibromatosis-associated tumorigenesis has been insight into the more general molecular and cellular bases of nervous system tumors...
  5. Yang F, Ingram D, Chen S, Zhu Y, Yuan J, Li X, et al. Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell. 2008;135:437-48 pubmed publisher
    ..Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation. ..
  6. Boyanapalli M, Lahoud O, Messiaen L, Kim B, Anderle de Sylor M, Duckett S, et al. Neurofibromin binds to caveolin-1 and regulates ras, FAK, and Akt. Biochem Biophys Res Commun. 2006;340:1200-8 pubmed
    ..These novel findings provide insight into possible signaling mechanisms of Nf1 and suggest that together Nf1 and Cav-1 may coordinately regulate cell growth and differentiation. ..
  7. Dasgupta B, Li W, Perry A, Gutmann D. Glioma formation in neurofibromatosis 1 reflects preferential activation of K-RAS in astrocytes. Cancer Res. 2005;65:236-45 pubmed
  8. Upadhyaya M. Genetic basis of tumorigenesis in NF1 malignant peripheral nerve sheath tumors. Front Biosci (Landmark Ed). 2011;16:937-51 pubmed
    ..Multidisciplinary collaborative efforts are clearly essential to fully decipher both the complex molecular basis of MPNST development and to define potential therapeutic targets...
  9. Wang H, Shih Y, Chen C, Chao H, Lee M, Hsueh Y. Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. J Clin Invest. 2011;121:4820-37 pubmed publisher
    ..The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation...
  10. Marrero D, Peralta R, Valdivia A, De la Mora A, Romero P, Parra M, et al. The neurofibromin 1 type I isoform predominance characterises female population affected by sporadic breast cancer: preliminary data. J Clin Pathol. 2012;65:419-23 pubmed publisher
    b>Neurofibromin 1 (NF1) as a tumour suppressor gene can give rise to several transcripts by an alternative splicing event, generated at least for CELF cofactors...
  11. Powers J, Evinger M, Zhi J, Picard K, Tischler A. Pheochromocytomas in Nf1 knockout mice express a neural progenitor gene expression profile. Neuroscience. 2007;147:928-37 pubmed
  12. Paschou M, Doxakis E. Neurofibromin 1 is a miRNA target in neurons. PLoS ONE. 2012;7:e46773 pubmed publisher
    Mutations of the neurofibromin 1 gene cause neurofibromatosis type 1, a disease in which learning and behavioral abnormalities are common. The disease is completely penetrant but shows variable phenotypic expression in patients...
  13. Lin Y, Hsueh Y. Neurofibromin interacts with CRMP-2 and CRMP-4 in rat brain. Biochem Biophys Res Commun. 2008;369:747-52 pubmed publisher
  14. Spurlock G, Knight S, Thomas N, Kiehl T, Guha A, Upadhyaya M. Molecular evolution of a neurofibroma to malignant peripheral nerve sheath tumor (MPNST) in an NF1 patient: correlation between histopathological, clinical and molecular findings. J Cancer Res Clin Oncol. 2010;136:1869-80 pubmed publisher
    ..This study analyzed the genetic alterations associated with this pathological heterogeneity in order to identify the genetic processes involved in transformation from a benign to an aggressive malignant tumor...
  15. Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel M, et al. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. 2010;31:E1506-18 pubmed publisher
    ..High-resolution array-CGH identified a new recurrent approximately 1.0 Mb microdeletion type, designated as type-3, with breakpoints in the paralogous regions middle NF1-REP-b and distal NF1-REP-c. ..
  16. Wiest V, Eisenbarth I, Schmegner C, Krone W, Assum G. Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers. Hum Mutat. 2003;22:423-7 pubmed
  17. Lee M, Stephenson D. Recent developments in neurofibromatosis type 1. Curr Opin Neurol. 2007;20:135-41 pubmed
    ..Recent advances in the clinical features and molecular genetics of NF1 will be discussed together with insights into the underlying pathomechanisms of NF1. ..
  18. Hawes J, Tuskan R, Reilly K. Nf1 expression is dependent on strain background: implications for tumor suppressor haploinsufficiency studies. Neurogenetics. 2007;8:121-30 pubmed
  19. Zhu C, Saberwal G, Lu Y, Platanias L, Eklund E. The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1. J Biol Chem. 2004;279:50874-85 pubmed
    ..quot; In these studies, we identify the gene encoding neurofibromin 1 (Nf1) as an ICSBP target gene, by chromatin immunoprecipitation...
  20. Wimmer K, Yao S, Claes K, Kehrer Sawatzki H, Tinschert S, De Raedt T, et al. Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer. 2006;45:265-76 pubmed
  21. Starinsky Elbaz S, Faigenbloom L, Friedman E, Stein R, Kloog Y. The pre-GAP-related domain of neurofibromin regulates cell migration through the LIM kinase/cofilin pathway. Mol Cell Neurosci. 2009;42:278-87 pubmed publisher
    ..Impairment of these cellular functions of neurofibromin provides novel insights into the invasiveness/progression of NF1-associated tumors. ..
  22. Le L, Parada L. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene. 2007;26:4609-16 pubmed
    ..Therefore, further understanding of the molecular interactions between Schwann cells and their environment will provide tools to develop new therapies aimed at delaying or preventing tumor formation in Nf1 patients. ..
  23. Diwakar G, Zhang D, Jiang S, Hornyak T. Neurofibromin as a regulator of melanocyte development and differentiation. J Cell Sci. 2008;121:167-77 pubmed
  24. Sabbagh A, Pasmant E, Laurendeau I, Parfait B, Barbarot S, Guillot B, et al. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet. 2009;18:2768-78 pubmed publisher
    ..Taken together, our results provided evidence that genetic modifiers, unlinked to the NF1 locus, contribute to the variable expressivity of the disease. ..
  25. Joseph N, Mosher J, Buchstaller J, Snider P, McKeever P, Lim M, et al. The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells. Cancer Cell. 2008;13:129-40 pubmed publisher
    ..Tumors appeared to arise from differentiated glia, not NCSCs. ..
  26. Trovó Marqui A, Tajara E. Neurofibromin: a general outlook. Clin Genet. 2006;70:1-13 pubmed
    ..2, and has different biochemical functions, including association to microtubules and participation in several signaling pathways. Alterations in this protein are responsible for a phacomatosis named neurofibromatosis type 1. ..
  27. De Luca A, Schirinzi A, Buccino A, Bottillo I, Sinibaldi L, Torrente I, et al. Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. Hum Mutat. 2004;23:629 pubmed
    ..Fifteen sequence variants likely to represent non-pathogenic polymorphisms were observed at the NF1 locus. Genotype-phenotype analysis was unable to detect any obvious correlation. ..
  28. Stowe I, Mercado E, Stowe T, Bell E, Oses Prieto J, Hernandez H, et al. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes Dev. 2012;26:1421-6 pubmed publisher
    ..This novel mechanism for the regulation of neurofibromin provides a molecular bridge for understanding the overlapping pathophysiology of NF1 and Legius syndrome...
  29. De Schepper S, Boucneau J, Westbroek W, Mommaas M, Onderwater J, Messiaen L, et al. Neurofibromatosis type 1 protein and amyloid precursor protein interact in normal human melanocytes and colocalize with melanosomes. J Invest Dermatol. 2006;126:653-9 pubmed
    ..We suggest that a complex between amyloid precursor protein, neurofibromin, and melanosomes might be important in melanosome transport, which could shed a new light on the etiopathogenesis of pigment-cell-related manifestations in NF1...
  30. Roth T, Petty E, Barald K. The role of steroid hormones in the NF1 phenotype: focus on pregnancy. Am J Med Genet A. 2008;146A:1624-33 pubmed publisher
    ..However, in this review, we consider evidence from the literature that both direct hormonal influence on tumor growth and on angiogenesis may contribute to these effects...
  31. Alwan S, Armstrong L, Joe H, Birch P, Szudek J, Friedman J. Associations of osseous abnormalities in Neurofibromatosis 1. Am J Med Genet A. 2007;143A:1326-33 pubmed
  32. Patrakitkomjorn S, Kobayashi D, Morikawa T, Wilson M, Tsubota N, Irie A, et al. Neurofibromatosis type 1 (NF1) tumor suppressor, neurofibromin, regulates the neuronal differentiation of PC12 cells via its associating protein, CRMP-2. J Biol Chem. 2008;283:9399-413 pubmed publisher
  33. Warrington N, Woerner B, Daginakatte G, Dasgupta B, Perry A, Gutmann D, et al. Spatiotemporal differences in CXCL12 expression and cyclic AMP underlie the unique pattern of optic glioma growth in neurofibromatosis type 1. Cancer Res. 2007;67:8588-95 pubmed
    ..Collectively, these studies provide a mechanism for the unique pattern of NF1-associated glioma growth. ..
  34. Xu J, Ismat F, Wang T, Yang J, Epstein J. NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Circulation. 2007;116:2148-56 pubmed
    ..These results suggest opportunities for targeted therapeutics in the prevention and treatment of NF1-related vascular disease and in the treatment of neointimal proliferation in other settings. ..
  35. Wang Y, Kim E, Wang X, Novitch B, Yoshikawa K, Chang L, et al. ERK inhibition rescues defects in fate specification of Nf1-deficient neural progenitors and brain abnormalities. Cell. 2012;150:816-30 pubmed publisher
    ..This study reveals a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis and identifies a potential therapeutic window for treating NF1-associated brain abnormalities. ..
  36. Wallace M, Pfefferle A, Shen L, McNairn A, Cerami E, Fallon B, et al. Comparative oncogenomics implicates the neurofibromin 1 gene (NF1) as a breast cancer driver. Genetics. 2012;192:385-96 pubmed publisher
    ..Chaos3 tumors underwent recurrent copy number alterations (CNAs), particularly deletion of the RAS inhibitor Neurofibromin 1 (Nf1) in nearly all cases. These overlap with human CNAs including NF1, which is deleted or mutated in 27...
  37. Liu C, Sage J, Miller M, Verhaak R, Hippenmeyer S, Vogel H, et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell. 2011;146:209-21 pubmed publisher
    ..Our findings suggest OPCs as the cell of origin in this model, even when initial mutations occur in NSCs, and highlight the importance of analyzing premalignant stages to identify the cancer cell of origin. ..
  38. De Schepper S, Boucneau J, Lambert J, Messiaen L, Naeyaert J. Pigment cell-related manifestations in neurofibromatosis type 1: an overview. Pigment Cell Res. 2005;18:13-24 pubmed
    ..Finally, we want to address the relationship between malignant melanoma and NF1. ..
  39. Leondaritis G, Petrikkos L, Mangoura D. Regulation of the Ras-GTPase activating protein neurofibromin by C-tail phosphorylation: implications for protein kinase C/Ras/extracellular signal-regulated kinase 1/2 pathway signaling and neuronal differentiation. J Neurochem. 2009;109:573-83 pubmed publisher
  40. Turbyville T, Gürsel D, Tuskan R, Walrath J, Lipschultz C, Lockett S, et al. Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner. Mol Cancer Ther. 2010;9:1234-43 pubmed publisher
  41. Brennan C, Momota H, Hambardzumyan D, Ozawa T, Tandon A, Pedraza A, et al. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS ONE. 2009;4:e7752 pubmed publisher
    ..The associated signaling activities correlating with these sentinel alterations provide insight into glioma biology and therapeutic strategies. ..
  42. Zhu H, Hinman M, Hasman R, Mehta P, Lou H. Regulation of neuron-specific alternative splicing of neurofibromatosis type 1 pre-mRNA. Mol Cell Biol. 2008;28:1240-51 pubmed
    ..In addition to providing the first mechanistic insight into tissue-specific control of NF1 splicing, these studies establish a novel strategy whereby Hu proteins regulate RNA processing. ..
  43. Banerjee S, Crouse N, Emnett R, Gianino S, Gutmann D. Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner. Proc Natl Acad Sci U S A. 2011;108:15996-6001 pubmed publisher
    ..Collectively, these findings establish TSC/Rheb-independent mechanisms for mTOR-dependent glial cell growth control and gliomagenesis relevant to the design of therapies for individuals with glioma. ..
  44. Brown J, Diggs Andrews K, Gianino S, Gutmann D. Neurofibromatosis-1 heterozygosity impairs CNS neuronal morphology in a cAMP/PKA/ROCK-dependent manner. Mol Cell Neurosci. 2012;49:13-22 pubmed publisher
  45. Marui T, Hashimoto O, Nanba E, Kato C, Tochigi M, Umekage T, et al. Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population. Am J Med Genet B Neuropsychiatr Genet. 2004;131B:43-7 pubmed
    ..This may suggest an involvement of the NF1 locus in susceptibility to autism, although further investigations are recommended. ..
  46. Tan M, Zhao Y, Kim S, Liu M, Jia L, Saunders T, et al. SAG/RBX2/ROC2 E3 ubiquitin ligase is essential for vascular and neural development by targeting NF1 for degradation. Dev Cell. 2011;21:1062-76 pubmed publisher
    ..Collectively, our study identifies NF1 as a physiological substrate of SAG-CUL1-FBXW7 E3 ligase and establishes a ubiquitin-dependent regulatory mechanism for the NF1-RAS pathway during embryogenesis. ..
  47. Xu J, Ismat F, Wang T, Lu M, Antonucci N, Epstein J. Cardiomyocyte-specific loss of neurofibromin promotes cardiac hypertrophy and dysfunction. Circ Res. 2009;105:304-11 pubmed publisher
    ..This report describes a critical role of Nf1 in the regulation of cardiac growth and function. Activation of pathways known to be involved in cardiac hypertrophy and dysfunction are seen with the loss of myocardial neurofibromin. ..
  48. Cui Y, Costa R, Murphy G, Elgersma Y, Zhu Y, Gutmann D, et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell. 2008;135:549-60 pubmed publisher
    ..Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning...
  49. Mangoura D, Sun Y, Li C, Singh D, Gutmann D, Flores A, et al. Phosphorylation of neurofibromin by PKC is a possible molecular switch in EGF receptor signaling in neural cells. Oncogene. 2006;25:735-45 pubmed
    ..Our data may suggest a novel mechanism for regulating biological responses to EGF and provide a new aspect for the understanding of the aberrant proliferation seen in the CNS of children with NF1. ..
  50. Zhu Y, Harada T, Liu L, Lush M, Guignard F, Harada C, et al. Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development. 2005;132:5577-88 pubmed
    ..These data point to hyperproliferative glial progenitors as the source of the optic tumors and provide a genetic model for NF1-associated astrogliosis and optic glioma. ..
  51. . Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061-8 pubmed publisher
    ..Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer. ..
  52. Griffiths S, Thompson P, Frayling I, Upadhyaya M. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6:21-34 pubmed
  53. Lin Y, Lei Y, Hong C, Hsueh Y. Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway. J Cell Biol. 2007;177:829-41 pubmed
    ..This study reveals a novel signaling pathway in which syndecan-2 activates PKA via neurofibromin and PKA consequently phosphorylates Ena/VASP, promoting filopodia and spine formation. ..