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

Stable Identifier
R-HSA-6802837
Type
Reaction [transition]
Species
Homo sapiens
Compartment
cytosol
ReviewStatus
5/5
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Loss-of-function NF1 variants don't stimulate RAS GTPase activity
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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
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Nature 2008
19467855 The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

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Curr. Opin. Genet. Dev. 2009
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Nature 2008
9668168 Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1

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24576830 Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence

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Science 2008
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Nature 1992
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Cancer Discov 2013
8563751 Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells

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Nat. Genet. 1996
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Sci Signal 2013
1568246 Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis

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

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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
Participants
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Participates
as an event of
Normal reaction
RAS GAPs stimulate RAS GTPase activity (Homo sapiens)
Functional status

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

Normal Entity
Disease Entity
Status
Disease
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
Authored
Rothfels, K  (2015-08-10)
Reviewed
Stephens, RM  (2016-08-05)
Created
Rothfels, K  (2015-10-02)
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