Neurofibromin 1

NF1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2D4Q, 2E2X, 3P7Z, 3PEG, 3PG7
Identifiers
Aliases	NF1, NFNS, VRNF, WSS, neurofibromin 1
External IDs	MGI: 97306 HomoloGene: 141252 GeneCards: NF1
Gene ontology Molecular function • phosphatidylcholine binding • protein binding • phosphatidylethanolamine binding • lipid binding • GTPase activator activity Cellular component • cytosol • membrane • intrinsic component of the cytoplasmic side of the plasma membrane • nucleolus • axon • dendrite • presynapse • cytoplasm • nucleus Biological process • cellular response to heat • regulation of angiogenesis • negative regulation of cell-matrix adhesion • positive regulation of extrinsic apoptotic signaling pathway in absence of ligand • observational learning • negative regulation of cell proliferation • negative regulation of astrocyte differentiation • regulation of long-term neuronal synaptic plasticity • regulation of MAPK cascade • regulation of GTPase activity • glutamate secretion, neurotransmission • amygdala development • negative regulation of Rac protein signal transduction • neural tube development • cognition • negative regulation of cell migration • regulation of gene expression • positive regulation of extrinsic apoptotic signaling pathway via death domain receptors • negative regulation of neurotransmitter secretion • positive regulation of endothelial cell proliferation • gamma-aminobutyric acid secretion, neurotransmission • negative regulation of osteoclast differentiation • negative regulation of endothelial cell proliferation • regulation of blood vessel endothelial cell migration • regulation of cell proliferation • regulation of long-term synaptic potentiation • negative regulation of angiogenesis • skeletal muscle tissue development • regulation of synaptic transmission, GABAergic • extrinsic apoptotic signaling pathway via death domain receptors • signal transduction • positive regulation of GTPase activity • Schwann cell development • adrenal gland development • spinal cord development • MAPK cascade • phosphatidylinositol 3-kinase signaling • heart development • positive regulation of neuron apoptotic process • negative regulation of transcription factor import into nucleus • peripheral nervous system development • wound healing • sympathetic nervous system development • osteoblast differentiation • positive regulation of apoptotic process • negative regulation of fibroblast proliferation • forebrain astrocyte development • metanephros development • negative regulation of MAP kinase activity • pigmentation • liver development • visual learning • regulation of glial cell differentiation • artery morphogenesis • positive regulation of adenylate cyclase activity • negative regulation of Ras protein signal transduction • regulation of bone resorption • extracellular matrix organization • actin cytoskeleton organization • cerebral cortex development • negative regulation of protein kinase activity • Ras protein signal transduction • forebrain morphogenesis • negative regulation of oligodendrocyte differentiation • regulation of cell-matrix adhesion • smooth muscle tissue development • brain development • collagen fibril organization • myelination in peripheral nervous system • camera-type eye morphogenesis • cell communication • response to hypoxia • negative regulation of neuroblast proliferation • negative regulation of MAPK cascade Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4763	18015
Ensembl	ENSG00000196712	ENSMUSG00000020716
UniProt	P21359	Q04690
RefSeq (mRNA)	NM_000267 NM_001042492 NM_001128147	NM_010897
RefSeq (protein)	NP_000258.1 NP_001035957.1 NP_001121619.1	NP_035027.1
Location (UCSC)	Chr 17: 31.09 – 31.38 Mb	Chr 11: 79.34 – 79.58 Mb
PubMed search	[1]	[2]
Wikidata

Neurofibromin 1 also known as neurofibromatosis-related protein NF-1 is a protein that in humans is encoded by the NF1 gene.^[3] Mutations in the NF1 gene are associated with neurofibromatosis type I (also known as von Recklinghausen disease) and Watson syndrome.^[4]

Function

NF1 encodes the protein neurofibromin, which appears to be a negative regulator of the ras signal transduction pathway. Neurofibromin is produced in many types of cells, including nerve and specialized cells such as the oligodendrocytes and also the Schwann cells surrounding the nerve cells. These cells are involved in formation of mylein sheaths and hence provide fatty covering to certain nerve cells and thus insulating and protecting them.^[5]

NF1 is found within the mammalian postsynapse, where it is known to bind to the NMDA receptor complex. It has been found to lead to learning deficits, and it is suspected that this is a result of its regulation of the Ras pathway. It is known to regulate the GTPase HRAS, causing the hydrolyzation of GTP and thereby inactivating it.^[6] Within the synapse HRAS is known to activate Src, which itself phosphorylates GRIN2A, leading to its inclusion in the synaptic membrane.

NF1 is also known to interact with CASK through syndecan, a protein which is involved in the KIF17/ABPA1/CASK/LIN7A complex, which is involved in trafficking GRIN2B to the synapse. This suggests that NF1 has a role in the transportation of the NMDA receptor subunits to the synapse and its membrane. NF1 is also believed to be involved in the synaptic ATP-PKA-cAMP pathway, through modulation of adenylyl cyclase. It is also known to bind the caveolin 1, a protein which regulates p21ras, PKC and growth response factors.^[6]

Clinical significance

Mutations linked to neurofibromatosis type 1 led to the identification of the NF1 gene. The neurofibromin gene may be mutated in thousands of ways, resulting in many possible clinical outcomes.^[7] In addition to neurofibromatosis type I, mutations in NF1 can also lead to juvenile myelomonocytic leukemia, Watson syndrome,^[8] and breast cancer.^[9] Types of mutations include frameshift, nonsense, missense, splicing alteration and deletion mutations, and loss of heterozygosity.^{[10][11][12][13]}

RNA editing

NF1 mRNA editing can modify disease in humans.^[14][15]

Type

The type of editing is a cytidine to uridine (C to U) site specific deamination. The editing site in NF1 mRNA was determined to have a high homology to the ApoB editing site where double stranded mRNA undergoes editing by the ApoB holoenzyme.^[16] This alluded to the same holoenzyme involved in ApoB mRNA editing maybe involved in editing of NF1.^[17] There are at least four different alternatively spliced forms of the protein, two of which are better defined. They differ by the inclusion of exon 23A. Recent experiments have shown that apobec-1 is indeed expressed outside the gastrointestinal luminal tract in some tumors and the inclusion of downstream exon 23a is preferentially found in these edited transcripts. These two features distinguishes them from tumors where RNA editing does not occur.^[18]

Location

The NF1 gene is located on long arm of chromosome 17 at position 11.2(17q11.2).^[19] The cytidine in the arginine codon (CGA) is deaminated to a uracil creating an inframe translational stop codon. The editing site is located at nucleotide position 2914. A region (nucleotides 2909-2930) was found to have a high homology to that found in the 21 nucleotide editing region of ApoB mRNA. It was suggested that the same editsome involved in ApoB mRNA editing may also be involved in NF1 mRNA editing. However the 6 nucleotide stretch from the edited cytidine and the start of the mooring sequence is two nucleotides longer than the ideal sequence required for ApoB mRNA editing. Also the region contains 2 guanidines which would be tolerated but again would not be ideal for ApoB mRNA editing. The mooring sequence and regulatory sequence are thought to be sufficient for editing to occur by ApoB mRNA editing machinery. This was determined by site mutagenesis experiments.^[20]

Regulation

NF1 RNA editing is not regulated by limited amounts of APOBEC-1. This implies that different factors are involved in NF1 mRNA editing than those associated with ApoB RNA editing. It is thought that different trans acting factors may be involved in the two editing processes.^[16] Also, the region surrounding the editing region in NF1 mRNA is GC rich instead of the preferred AT rich sequence found in ApoB mRNA editing site. This reason as well as the longer spacer element of NF1 mRNA than that of ApoB mRNA are thought to be factors in the difference in frequency of editing of the two mRNAs (20% NF1, 90% ApoB).^[21] Editing occurs in a higher frequency in tumours compared to the relative normal tissues.^[16] There is a higher frequency of editing in the NF1 mRNA which includes Exon 23A in tumors.^[18]

Conservation

The editing site is thought not to be conserved as editing of NF1 mRNA does not occur in the rat or mouse but these species do express several alternatively spliced mRNAs.^[16][22] One of these alternatively spliced isoforms known as TYPE III in rats and mice introduces a frameshift that introduces a stop codon by inclusion of a 41 base pair exon.^[15]

Consequences

Structure

Editing results in a codon change from an arginine codon (CGA) to an in frame stop codon (UGA) due to a base change at nucleotide 2914. The introduction of an inframe stop codon results in a translated protein that is truncated. The translated protein is thought to be lacking its GAP Related Domain (GRD) that shares a homology to mammalian GTPase activating (GAP) domain and yeast inhibitor of RAS protein 1 and 2 domains.^[16]

Function

The gene product is neurofibromin, a tumor-suppressor, a region of which functions as a GTPase-activating protein shown to be involved in negative regulation of the RAS pathway.^[15][23] NF1 mRNA editing has been detected in a wide range of tissues. Editing results in a truncated protein being translated that does not contain this region. The GTPase region has a high homology to mammalian and yeast (GAPs) which would suggest that neurofibromin plays a role in negative regulation of RAS signal transduction pathways. It is thought that editing therefore would result in the loss of the protein's tumor suppressor activity.^[14][24][25] This corresponds to the observed increase in editing in tumors compared to normal tissue, however further research into the role of mRNA editing of NF1 mRNA in pathogenesis in tumours needs to be undertaken.^[16][22] There is a correlation in an increase of editing in some tumors and the degree of malignancy of the tumor suggesting a relationship between the two.^[15] Recently further evidence of the role of editing in pathogenesis in tumors.It was observed that C to U editing of NF1 mRNA occurs in a fraction of tumor samples of NF1 patients where APOBEC-1 is also expressed. This was an important find as was the first time APOBEC-1 expression was proven experimentally outside the luminal cells of the tract.^[18] The N-terminus of the protein has a region demonstrated to be able to bind microtubules. It has been suggested that since the edited protein still retains this region, that a function of this editing is to displace microtubules from the ffull-lengthneurofiromin protein. This would liberate the full-length protein to interact with RAS.^[22][26]

Neurofibromatosis

It is thought that RNA editing may account for the wide variation in phenotype of this condition even among siblings.^[27] Also, 50% of new cases have new mutations. The frequency is too high to explain these cases as spontaneous mutations, therefore RNA editing of NF1 rna may provide an alternative reason for the variation of phenotype.^[17] More than 1000 NF1 mutations that cause nerufibromatosis type 1 have been identified and some belonging to certain families of classification.Research indicates that the formation of neurofibromas requires the interaction of Schwann cells with other cells, including mast cells. Mast cells are normally involved in wound healing and tissue repair.

Model organisms

Model organisms have been used in the study of NF1 function. A conditional knockout mouse line, called Nf1^{tm1a(KOMP)Wtsi[34][35]} was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.^[36][37][38]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[32][39] Twenty six tests were carried out on mutant mice and four significant abnormalities were observed.^[32] Over half the homozygous mutant embryos identified during gestation were dead, and in a separate study none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice: females displayed abnormal hair cycling while males had an decreased B cell number and an increased monocyte cell number.^[32]

Patent

The neurofibromatosis gene was patented by the University of Michigan, with the initial filing in 1991 and the patent granted in 2001.^[40]

See also

• SPRED1 gene

References

Further reading

External links

• GeneReviews/NCBI/NIH/UW entry on Neurofibromatosis 1
• Human Gene NF1 (uc002hgf.1)
• neurofibromin 1 from GeneCards
• Database of RNA editing

PDB gallery
1nf1: THE GAP RELATED DOMAIN OF NEUROFIBROMIN  2d4q: Crystal structure of the Sec-PH domain of the human neurofibromatosis type 1 protein