Neurofibromin and suppression of tumorigenesis: beyond the GAP

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease and one of the most common inherited tumor predisposition syndromes, affecting 1 in 3000 individuals worldwide. The NF1 gene encodes neurofibromin, a large protein with RAS GTP-ase activating (RAS-GAP) activity, and loss of NF1 results in increased RAS signaling. Neurofibromin contains many other domains, and there is considerable evidence that these domains play a role in some manifestations of NF1. Investigating the role of these domains as well as the various signaling pathways that neurofibromin regulates and interacts with will provide a better understanding of how neurofibromin acts to suppress tumor development and potentially open new therapeutic avenues. In this review, we discuss what is known about the structure of neurofibromin, its interactions with other proteins and signaling pathways, its role in development and differentiation, and its function as a tumor suppressor. Finally, we discuss the latest research on potential therapeutics for neurofibromin-deficient neoplasms.

Fig. 1. Diagram of the clinical manifestations of NF1.

Individuals with NF1 have a wide spectrum of clinical manifestations, from café-au-lait macules to benign neurofibroma to malignant peripheral nerve sheath tumor (MPNST) as well as cognitive symptoms including learning disabilities and attention deficit disorder [1, 2]. ADHD attention-deficit/hyperactivity disorder, CNS central nervous system, GIST gastrointestinal stromal tumor, JCML juvenile chronic myelogenous leukemia, PNS peripheral nervous system. Created with BioRender.com.

Fig. 2. Domains of the neurofibromin protein and proteins that directly interact with those domains.

Schematic presentation of known domains of NF1. Numbers indicate the amino acid residues comprising the domains. (Top) Diagram shows neurofibromin regulation at the level of mRNA splicing. Proteins shown in red result regulate splicing that excludes exon 30alt31, while green indicates inclusion of that exon. (Bottom) Proteins that directly interact with neurofibromin are shown in green for positive regulation and red for negative regulation [, , , –38, 44, 67, 68, 73, 111]. Domains: CBD caveolin-binding domains, CSRD cysteine and serinerich domain, CTD C-terminal domain, GRD RAS-GAP-related domain, HLR HEAT-like repeats, LRD leucine-rich domain, PH pleckstrin homology, SBR syndecan-binding region, TBD tubulin-binding domain. Proteins: ALK anaplastic lymphoma kinase, CELF CUG-BP1 and ETR-3-like factors, CRMP-2 collapsin response mediator protein 2, FAK focal adhesion kinase, GPCRs G-Protein-Coupled Receptors, LIMK2 LIM Domain Kinase 2, LRPPRC leucine-rich pentatricopeptide repeat motif-containing protein, Spred1 Sprouty-related, EVH1 domain-containing protein 1. TIA-1 T-cell intracellular antigen 1. Created with BioRender.com.

Fig. 3. Downstream signaling of NF1: molecular functions of neurofibromin in key biological signaling pathways.

Known signaling pathways downstream of NF1 are shown [, –, , , , –, –90, 103, 111] Created with BioRender.com.

Fig. 4. Clinical manifestations of NF1.

a Cutaneous neurofibroma on the back. b Plexiform neurofibroma on the right ankle.

Fig. 5. NF1 genotype-phenotype correlations.

NF1 mutations reported to correlate with particular phenotypes are indicated [, , –, –198]. Created with BioRender.com.

Fig. 6. List of sporadic tumors with NF1 mutation.

The range of frequency (%) of NF1 mutations reported in other cancer types is shown [, , –, –286].