Loss-of-function NF1 variants don't stimulate RAS GTPase activity

Stable Identifier
Reaction [transition]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

NF1 is a RAS GTPase activating protein (GAP) that promotes the conversion of the active RAS:GTP to the inactive RAS:GDP form (reviewed in King et al, 2013). Germline loss-of-function mutations in NF1 are associated with neurofibromatosis 1, an autosomal dominant disorder that causes aberrant activation of the RAS signaling pathway (reviewed in Tidyman and Rauen, 2009). More recently, somatic loss-of-function mutations in NF1 have been identified in a number of cancers such as glioblastoma, lung adenocarcinoma, breast and ovarian cancers, leukemia and neuroblastoma, making NF1 a tumor suppressor (Cancer Genome Atlas Research Network, 2008; Parsons et al, 2008; McGillicuddy et al, 2009; Ding et al, 2008; The et al, 1993; Holzel et al, 2010; Maertens et al, 2013; Whittaker et al, 2013; reviewed in Maertens and Cichowski, 2014). Cancer-associated lesions in the NF1 gene range from homozygous deletions of the entire gene to missense or frameshift mutations that truncate and destabilize the protein; these variant alleles are often expressed at very low levels or not at all and where examined, most cells appear to have compromised GAP activities (Basu et al, 1992; De CLue et al, 1992; Bollag et al, 1996; Klose et al, 1998; Updahyaya et al, 1997; Krauthammer et al, 2015; Nissan et al, 2014; Thomas et al, 2012; reviewed in Maertens and Cichowski, 2014).

Literature References
PubMed ID Title Journal Year
18772890 Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Cancer Genome Atlas Research Network, -

Nature 2008
19467855 The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

Tidyman, WE, Rauen, KA

Curr. Opin. Genet. Dev. 2009
26214590 Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas

Narayan, D, Straub, R, McCusker, JP, Kluger, HM, Ariyan, S, Pornputtapong, N, Ma, S, Schlessinger, J, Sznol, M, Krauthammer, M, Serin, M, Mane, S, Bosenberg, M, Wu, C, Halaban, R, Lifton, RP, Evans, P, Bacchiocchi, A, Kong, Y, Cheng, E

Nat. Genet. 2015
18948947 Somatic mutations affect key pathways in lung adenocarcinoma

Abbott, R, Fennell, T, Milosavljevic, A, Weinstock, GM, Yoshizawa, A, Hawes, AC, Varmus, HE, Good, PJ, Haipek, C, Hanna, M, Thomas, RK, Hall, O, Onofrio, RC, Beer, DG, Gonzalez-Garay, ML, Lander, ES, Fulton, L, Wistuba, II, Pao, W, Giordano, T, Ladanyi, M, Mardis, ER, Osborne, JR, Zhu, Y, Chen, K, McLellan, MD, Broderick, S, Kraja, A, Wendl, MC, Sawyer, CS, Shen, H, Province, MA, Tonon, G, Spitz, MR, Miner, TL, Larson, DE, Robinson, J, Roth, JA, Schmidt, H, Zhang, Q, Dooling, DJ, Dunford-Shore, BH, Greulich, H, Gibbs, RA, Jhangiani, SN, Weir, BA, Lin, L, Winckler, W, Muzny, DM, Ziaugra, L, Zody, MC, Fewell, G, Chirieac, LR, Meyerson, M, Fulton, RS, Scherer, SE, Sabo, A, Lewis, LR, Ng, B, Vickery, T, Orringer, MB, Wheeler, DA, Mathew, T, Ren, Y, Koboldt, DC, Sougnez, C, Gabriel, SB, Chang, AC, Crosby, SD, Clerc, K, Ding, L, Tang, Y, Meyer, R, Cibulskis, K, Metcalf, GA, Morgan, MB, Baldwin, J, Ozenberger, B, Sander, S, Pohl, C, Yao, J, Dutt, A, Lawrence, MS, Wilson, RK, Getz, G, Travis, WD, Shi, X, Johnson, BE, Watson, MA, Zhao, X

Nature 2008
9668168 Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1

Scheffzek, K, Klose, A, Wittinghofer, A, Peters, H, Ahmadian, MR, Schuelke, M, Schmitz, F, Gewies, A, Kaufmann, D, Hoffmeyer, S, Nürnberg, P

Hum. Mol. Genet. 1998
22108604 Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

Brems, H, Chuzhanova, N, Spurlock, G, Thomas, L, Upadhyaya, M, Cooper, DN, Eudall, C, Legius, E, Mort, M, Thomas, NS, Hamby, SE

Eur. J. Hum. Genet. 2012
24576830 Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence

Schultz, N, Tiwari, S, Liu, C, Ramirez, R, Hanrahan, AJ, Nissan, MH, Ribas, A, Yaeger, R, Taylor, BS, Merghoub, T, Pratilas, CA, Yao, Z, Won, H, Chapman, PB, Berger, MF, Jones, AM, Kong, L, Solit, DB, Rosen, N

Cancer Res. 2014
8490657 Neurofibromatosis type 1 gene mutations in neuroblastoma

Hannigan, GE, Jacoby, LB, Gusella, JF, The, I, Bernards, A, Murthy, AE, Menon, AG

Nat. Genet. 1993
18772396 An integrated genomic analysis of human glioblastoma multiforme

Bigner, DD, McLendon, R, Gallia, GL, Strausberg, RL, Karchin, R, Mankoo, P, Papadopoulos, N, Marie, SK, Parsons, DW, Hartigan, J, Kinzler, KW, Nikolsky, Y, Vogelstein, B, Diaz Jr, LA, Angenendt, P, Shinjo, SM, Velculescu, VE, Lin, JC, Jones, S, Parmigiani, G, Zhang, X, Leary, RJ, Yan, H, Smith, DR, Nikolskaya, T, Riggins, GJ, Keir, S, Olivi, A, Rasheed, BA, Siu, IM, Carter, H, Tekleab, H, Busam, DA

Science 2008
1570015 Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients

Basu, TN, Collins, FS, Downward, J, Glover, TW, Fletcher, JA, Gutmann, DH

Nature 1992
23171796 Elucidating distinct roles for NF1 in melanomagenesis

Granter, S, Cichowski, K, Johnson, B, Messiaen, L, Cooper, ZA, Wargo, JA, Flaherty, K, Frederick, DT, Bronson, RT, McMahon, M, Hollstein, P, Marais, R, Maertens, O

Cancer Discov 2013
8563751 Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells

Freedman, MH, Adler, F, Jacks, T, McCormick, F, Shannon, K, Shih, S, Lange, BJ, Thompson, P, Zhang, YY, Clapp, DW, Bollag, G

Nat. Genet. 1996
23443682 Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis

Lapinski, PE, Lubeck, BA, King, PD

Sci Signal 2013
1568246 Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis

DeClue, JE, Ratner, N, Diehl, SR, Lowy, DR, Papageorge, AG, Fletcher, JA, Vass, WC

Cell 1992
20655465 NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome

Asgharzadeh, S, Bernards, R, Versteeg, R, Messiaen, L, Seeger, RC, Caron, H, Huang, S, Lakeman, A, Xie, J, Nijkamp, W, Callens, T, Koster, J, Hölzel, M, Ora, I

Cell 2010
19573811 Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis

Stemmer-Rachamimov, AO, Moldenhauer, G, Fromm, JA, Liau, LM, Kubek, S, Cichowski, K, Parret, A, Mellinghoff, IK, Messiaen, L, Mischel, PS, Sawyers, CL, De Raedt, T, Scheffzek, K, Seiler, J, Beroukhim, R, Cloughesy, TF, Williams, SM, Brennan, C, McGillicuddy, LT, Johnson, BW, Hollstein, PE, Nghiemphu, P

Cancer Cell 2009
Normal reaction
Functional status

Loss of function of NF1 GTPase mutants:SPRED dimer:p21 RAS:GTP [plasma membrane]

Name Identifier Synonyms
neurofibromatosis DOID:8712 Neurofibromatosis 1, neurofibromatosis type IV, Acoustic neurofibromatosis, Recklinghausen's neurofibromatosis, neurofibromatosis type 4, central Neurofibromatosis, type IV neurofibromatosis of riccardi, neurofibromatosis type 1, neurofibromatosis type 2, peripheral Neurofibromatosis, von Reklinghausen disease
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Cite Us!